Substituted heteroarylamide analogs as mGluR5 negative allosteric modulators and methods of making and using the same

ABSTRACT

Disclosed are negative allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 61/243,378,filed Sep. 17, 2009, which is hereby incorporated herein by reference inits entirety.

ACKNOWLEDGMENT

This invention was made with government support under Grant no.1R01-DA023947-01 awarded by the National Institute on Drug Abuse (NIDA),under Grant no. 5R01-NS031373-15 awarded by the National Institute ofNeurological Disorders and Stroke (NINDS), and under Grant no.5R01-MH073676-04 awarded by the National Institute of Mental Health(NIMH). The United States government has certain rights in theinvention.

BACKGROUND

Glutamate (L-glutamic acid) is the major excitatory transmitter in themammalian central nervous system, exerting its effects through bothionotropic and metabotropic glutamate receptors. The metabotropicglutamater receptors (mGluRs) belong to family C (also known as family3) of the G-protein-coupled receptors (GPCRs). They are characterized bya seven transmembrane (7TM) α-helical domain connected via a cysteinerich-region to a large bi-lobed extracellular amino-terminal domain(FIG. 1). While the orthosteric binding site is contained in theamino-terminal domain, currently known allosteric binding sites residein the 7TM domain. The mGluR family comprises eight known mGluRsreceptor types (designated as mGluR1 through mGluR8). Several of thereceptor types are expressed as specific splice variants, e.g. mGluR5aand mGluR5b or mGluR8a, mGluR8b and mGluR8c. The family has beenclassified into three groups based on their structure, preferred signaltransduction mechanisms, and pharmacology. Group I receptors (mGluR1 andmGluR5) are coupled to Gαq, a process that results in stimulation ofphospholipase C and an increase in intracellular calcium and inositolphosphate levels. Group II receptors (mGluR2 and mGluR3) and group IIIreceptors (mGluR4, mGluR6, mGluR7, and mGluR8) are coupled to Gαi, whichleads to decreases in cyclic adenosine monophosphate (cAMP) levels.While the Group I receptors are predominately located postsynapticallyand typically enhance postsynaptic signaling, the group II and IIIreceptors are located presynaptically and typically have inhibitoryeffects on neurotransmitter release. Without wishing to be bound bytheory, increasing evidence indicates mGluRs play an important role inlasting changes in synaptic transmission, and studies of synapticplasticity in the Fmr1 knockout mouse have identified a connectionbetween the fragile X phenotype and mGluR signaling.

The identification of small molecule mGluR antagonists that bind at theorthosteric site has greatly increased the understanding of the rolesplayed by these receptors and their corresponding relation to disease.Because the majority of these antagonists were designed as analogs ofglutamate, they typically lack desired characteristics for drugstargeting mGluR such as oral bioavailability and/or distribution to thecentral nervous system (CNS). Moreover, because of the highly conservednature of the glutamate binding site, most orthosteric antagonists lackselectivity among the various mGluRs.

A more recent strategy that has been able to successfully deal with theaforementioned issues has been the design of compounds that bind themGluR at a site that is topographically distinct from the othostericbinding site, or an allosteric binding site. Selective negativeallosteric modulators (NAMs) are compounds that do not directlydeactivate receptors by themselves, but decrease the affinity of aglutamate-site agonist at its extracellular N-terminal binding site.Negative allosteric modulation is thus an attractive mechanism forinhibiting appropriate physiological receptor activation. Among the moststudied and characterized small molecules are the mGluR5NAMs,2-methyl-6-(phenylethynyl)pyridine (MPEP) and3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP). Both MPEP andMTEP have proven efficacious in numerous rodent models of disease,including those for drug addiction and pain as well as anxiety. Thecompounds were also able to inhibit transient lower esophageal sphincterrelaxation (TLESD), the major cause of gastroesophageal reflux disease(GERD), in dogs and ferrets. In addition, MPEP was efficacious in mousemodels of fragile X syndrome (FXS) and Parkinson's disease (PD) as wellas a baboon model of binge-eating disorder.

Although the utility of MPEP and MTEP as tool compounds has been clearlydemonstrated, both molecules have issues that complicate or preventtheir further development as therapeutic molecules. MPEP has been shownto directly inhibit the N-methyl-D-aspartate (NMDA) receptor activity athigher concentrations and is a positive allosteric modulator of mGluR4.While these selectivity issues are mitigated with MTEP, it is a potentinhibitor of cytochrome P450 1A2 and is efficiently cleared followingintravenous administration to rhesus monkeys.

Potential adverse effects of known mGluR5 NAMs, however, could reducetheir ultimate therapeutic utility. Further, conventional mGluR5receptor modulators which target the orthosteric binding site can lacksatisfactory aqueous solubility, exhibit poor oral bioavailability,and/or exhibit adverse effects. Therefore, there remains a need formethods and compositions that overcome these deficiencies and thateffectively provide selective negative allosteric modulators for themGluR5 receptor.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocompounds useful as negative allosteric modulators of the metabotropicglutamate receptor subtype 5 (mGluR5), methods of making same,pharmaceutical compositions comprising same, and methods of treatingdisorders associated with glutamate dysfunction using same.

Disclosed are compounds, or pharmaceutically acceptable salts thereof,having a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷; wherein W is CR⁶ or N;wherein Z is CR^(6a) or N; provided that only one of W and Z is N;wherein R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; whereinR¹ is substituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁶, when present, is selected from hydrogen, halogen, CN, C3-C4cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl;wherein each of R^(6a) and R^(6b) is independently selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6haloalkoxy; wherein R^(6a) is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R7is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl,C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino; and wherein eachR⁹, when present, is independently halogen, C1-C6 alkyl, C1-C6haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, NO₂, CN, SO₂R⁸,or COR⁸; wherein the compound exhibits partial or total inhibition ofmGluR5 response to glutamate as a decrease in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith rat mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a disclosed compound and apharmaceutically acceptable carrier.

Also disclosed are methods of making a compound comprising the step ofreacting a compound having a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein R² is hydrogen,halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy,amino, hydroxyl, alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸;wherein R³ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, and CN; wherein R⁴ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl,amino, alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the provisothat when A is N, then R⁴ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁷ is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and wherein R⁸is C1-C6 alkyl, C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino;with a second compound having a structure represented by a formula:

wherein X is a leaving group; wherein W is CR⁶ or N; wherein Z isCR^(6a) or N; provided that only one of W and Z is N; wherein R⁶, whenpresent, is selected from hydrogen, halogen, CN, C3-C4 cycloalkyl, C3-C4halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl; wherein each of R^(6a)and R^(6b) is independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and whereinR^(6a) is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl,C1-C6 alkoxy, and C1-C6 haloalkoxy, thereby forming a product having astructure represented by a formula:

Also disclosed are methods of making a compound comprising the step ofreacting a compound having a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein R² is hydrogen,halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy,amino, hydroxyl, alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸;wherein R³ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, and CN; wherein R⁴ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl,amino, alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the provisothat when A is N, then R⁴ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁷ is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and wherein R⁸is C1-C6 alkyl, C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino,with a second compound having a structure represented by a formula:

wherein X¹ and X² are independently selected from leaving groups;wherein W is CR⁶ or N; wherein Z is CR^(6a) or N; provided that only oneof W and Z is N; wherein R⁶, when present, is selected from hydrogen,halogen, CN, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, andC1-C6 haloalkyl; wherein each of R^(6a) and R^(6b) is independentlyselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, and C1-C6 haloalkoxy; and wherein R^(6c) is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6haloalkoxy, thereby forming a product having a structure represented bya formula:

Also disclosed are products of the disclosed methods.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a disclosed product and apharmaceutically acceptable carrier.

Also disclosed are methods for manufacturing a medicament comprisingcombining at least one disclosed compound or at least one disclosedproduct with a pharmaceutically acceptable carrier or diluent.

Also disclosed are methods for the treatment of a disorder associatedwith mGluR5 activity in a mammal comprising the step of administering tothe mammal at least one compound having a structure represented by aformula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein Q is CR^(6e) or N;wherein V is CR^(6b) or N; wherein W is CR⁶ or N; wherein Z is CR^(6a)or N; provided that 1-2 of Q, V, W, and Z are simultaneously N; R¹ isaryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R¹ issubstituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁶, when present, is selected from hydrogen, halogen, CN, C3-C4cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl;wherein R^(ha), when present, is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; whereinR^(6b), when present, is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R^(6c) isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, and C1-C6 haloalkoxy; wherein R⁷ is hydrogen, C1-C6 alkyl, orC1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl, C1-C6 cycloalkyl, amino,alkylamino, or dialkylamino; and wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; or a pharmaceuticallyacceptable salt thereof, in an effective amount to treat the disorder inthe mammal.

Also disclosed are methods for decreasing mGluR5 activity in a mammalcomprising the step of administering to the mammal at least one compoundhaving a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein Q is CR^(6c) or N;wherein V is CR^(6b) or N; wherein W is CR⁶ or N; wherein Z is CR^(6a)or N; provided that 1-2 of Q, V, W, and Z are simultaneously N; R¹ isaryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R¹ issubstituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁶, when present, is selected from hydrogen, halogen, CN, C3-C4cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl;wherein R^(ha), when present, is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; whereinR^(6b), when present, is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R^(6c) isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, and C1-C6 haloalkoxy; wherein R⁷ is hydrogen, C1-C6 alkyl, orC1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl, C1-C6 cycloalkyl, amino,alkylamino, or dialkylamino; and wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; or a pharmaceuticallyacceptable salt thereof, in an effective amount to decrease mGluR5activity in the mammal.

Also disclosed are methods for inhibiting mGluR5 activity in at leastone cell, comprising the step of contacting the at least one cell withat least one compound having a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein Q is CR^(6c) or N;wherein V is CR^(6b) or N; wherein W is CR⁶ or N; wherein Z is CR^(6a)or N; provided that 1-2 of Q, V, W, and Z are simultaneously N; R¹ isaryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R¹ issubstituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁶, when present, is selected from hydrogen, halogen, CN, C3-C4cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl;wherein R^(6a), when present, is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; whereinR^(6b), when present, is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R^(6c) isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, and C1-C6 haloalkoxy; wherein R⁷ is hydrogen, C1-C6 alkyl, orC1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl, C1-C6 cycloalkyl, amino,alkylamino, or dialkylamino; and wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; or a pharmaceuticallyacceptable salt thereof, in an effective amount to inhibit mGluR5activity in the at least one cell.

Also disclosed are uses of the disclosed compound or a disclosed producthaving a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein W is CR⁶ or N;wherein Z is CR^(6a) or N; provided that only one of W and Z is N; R¹ isaryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R¹ issubstituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁶, when present, is selected from hydrogen, halogen, CN, C3-C4cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl;wherein each of R^(6a) and R^(6b) is independently selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6haloalkoxy; wherein R^(6c) is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R⁷is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl,C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino; and wherein eachR⁹, when present, is independently halogen, C1-C6 alkyl, C1-C6haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, NO₂, CN, SO₂R⁸,or COR⁸; or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a disorder associatedwith glutamate dysfunction in a mammal.

Also disclosed are kits comprising at least one disclosed compound or atleast one disclosed product a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein W is CR⁶ or N;wherein Z is CR^(6a) or N; provided that only one of W and Z is N; R¹ isaryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R¹ issubstituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁶, when present, is selected from hydrogen, halogen, CN, C3-C4cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl;wherein each of R^(6a) and R^(6b) is independently selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6haloalkoxy; wherein R^(6c) is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R⁷is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl,C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino; and wherein eachR⁹, when present, is independently halogen, C1-C6 alkyl, C1-C6haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, NO₂, CN, SO₂R⁸,or COR⁸; or a pharmaceutically acceptable salt thereof, and one or moreof: at least one agent known to increase mGluR5 activity; at least oneagent known to decrease mGluR5 activity; at least one agent known totreat a neurological and/or psychiatric disorder; at least one agentknown to treat a disease of uncontrolled cellular proliferation; orinstructions for treating a disorder associated with glutamatedysfunction.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 is a schematic representation of an mGluR.

FIG. 2 illustrates allosteric modulation of mGluR5.

FIG. 3 shows representative data of the effect of an exemplary compoundin a mouse model of anxiolytic behavior.

FIG. 4 shows representative data of the effect of an exemplary compoundin a mouse model of anxiolytic behavior.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examples andFigures included herein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present invention is not entitledto antedate such publication by virtue of prior invention. Further, thedates of publication provided herein may be different from the actualpublication dates, which can require independent confirmation.

A. Definitions

As used herein, nomenclature for compounds, including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. When one or more stereochemical features are present,Cahn-Ingold-Prelog rules for stereochemistry can be employed todesignate stereochemical priority, E/Z specification, and the like. Oneof skill in the art can readily ascertain the structure of a compound ifgiven a name, either by systemic reduction of the compound structureusing naming conventions, or by commercially available software, such asCHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or can not occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “mGluR5 receptor negative allosteric modulator”refers to any exogenously administered compound or agent that directlyor indirectly inhibits the activity of the mGluR5 receptor in thepresence of the endogenous ligand (such as glutamate) in an animal, inparticular a mammal, for example a human. The term is synonymous withthe terms “mGluR5 receptor allosteric inhibitor,” “mGluR5 receptornoncompetitive inhibitor,” “mGluR5 receptor allosteric antagonist,” and“mGluR5 receptor noncompetitive antagonist.”

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects. In some aspects of the disclosedmethods, the subject has been diagnosed with a need for treatment of oneor more neurological and/or psychiatric disorder associated withglutamate dysfunction prior to the administering step. In some aspectsof the disclosed method, the subject has been diagnosed with a need fornegative allosteric modulation of metabotropic glutamate receptoractivity prior to the administering step. In some aspects of thedisclosed method, the subject has been diagnosed with a need for partialantagonism of metabotropic glutamate receptor activity prior to theadministering step.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In one aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein. For example,“diagnosed with a disorder treatable by modulation of mGluR5” meanshaving been subjected to a physical examination by a person of skill,for example, a physician, and found to have a condition that can bediagnosed or treated by a compound or composition that can modulatemGluR5. As a further example, “diagnosed with a need for modulation ofmGluR5” refers to having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditioncharacterized by mGluR5 activity. Such a diagnosis can be in referenceto a disorder, such as a neurodegenerative disease, and the like, asdiscussed herein. For example, the term “diagnosed with a need fornegative allosteric modulation of metabotropic glutamate receptoractivity” refers to having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditionthat can be diagnosed or treated by negative allosteric modulation ofmetabotropic glutamate receptor activity. For example, “diagnosed with aneed for partial antagonism of metabotropic glutamate receptor activity”means having been subjected to a physical examination by a person ofskill, for example, a physician, and found to have a condition that canbe diagnosed or treated by partial antagonism of metabotropic glutamatereceptor activity. For example, “diagnosed with a need for treatment ofone or more neurological and/or psychiatric disorder associated withglutamate dysfunction” means having been subjected to a physicalexamination by a person of skill, for example, a physician, and found tohave one or more neurological and/or psychiatric disorder associatedwith glutamate dysfunction.

As used herein, the phrase “identified to be in need of treatment for adisorder,” or the like, refers to selection of a subject based upon needfor treatment of the disorder. For example, a subject can be identifiedas having a need for treatment of a disorder (e.g., a disorder relatedto mGluR5 activity) based upon an earlier diagnosis by a person of skilland thereafter subjected to treatment for the disorder. It iscontemplated that the identification can, in one aspect, be performed bya person different from the person making the diagnosis. It is alsocontemplated, in a further aspect, that the administration can beperformed by one who subsequently performed the administration.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

The term “contacting” as used herein refers to bringing a disclosedcompound and a cell, target metabotropic glutamate receptor, or otherbiological entity together in such a manner that the compound can affectthe activity of the target (e.g., spliceosome, cell, etc.), eitherdirectly; i.e., by interacting with the target itself, or indirectly;i.e., by interacting with another molecule, co-factor, factor, orprotein on which the activity of the target is dependent.

As used herein, the term “effective amount” refers to an amount that issufficient to achieve the desired result or to have an effect on anundesired condition. For example, a “therapeutically effective amount”refers to an amount that is sufficient to achieve the desiredtherapeutic result or to have an effect on undesired symptoms, but isgenerally insufficient to cause adverse side affects. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration; the route of administration; the rate of excretion ofthe specific compound employed; the duration of the treatment; drugsused in combination or coincidental with the specific compound employedand like factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of a compound at levels lowerthan those required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration. Consequently, single dose compositions cancontain such amounts or submultiples thereof to make up the daily dose.The dosage can be adjusted by the individual physician in the event ofany contraindications. Dosage can vary, and can be administered in oneor more dose administrations daily, for one or several days. Guidancecan be found in the literature for appropriate dosages for given classesof pharmaceutical products. In further various aspects, a preparationcan be administered in a “prophylactically effective amount”; that is,an amount effective for prevention of a disease or condition.

As used herein, “EC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50% agonismof a biological process, or component of a process, including a protein,subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC₅₀ canrefer to the concentration of a substance that is required for 50%agonism in vivo, as further defined elsewhere herein. In a furtheraspect, EC₅₀ refers to the concentration of agonist that provokes aresponse halfway between the baseline and maximum response.

As used herein, “IC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process, or component of a process, includinga protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, anIC₅₀ can refer to the concentration of a substance that is required for50% inhibition in vivo, as further defined elsewhere herein. In afurther aspect, IC₅₀ refers to the half maximal (50%) inhibitoryconcentration (IC) of a substance.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH₂CH₂O— units in thepolyester, regardless of whether ethylene glycol was used to prepare thepolyester. Similarly, a sebacic acid residue in a polyester refers toone or more —CO(CH₂)₈CO— moieties in the polyester, regardless ofwhether the residue is obtained by reacting sebacic acid or an esterthereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkylgroup can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refersto an alkyl group that is substituted with one or more alkoxy groups, asdescribed below. The term “alkylamino” specifically refers to an alkylgroup that is substituted with one or more amino groups, as describedbelow, and the like. When “alkyl” is used in one instance and a specificterm such as “alkylalcohol” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“alkylalcohol” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Thecycloalkyl group and heterocycloalkyl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula (CH₂)_(a)—, where “a” is an integer of from 2to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² orOA¹-(OA²)_(a)-OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbornenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Thecycloalkenyl group and heterocycloalkenyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” alsoincludes “heteroaryl,” which is defined as a group that contains anaromatic group that has at least one heteroatom incorporated within thering of the aromatic group. Examples of heteroatoms include, but are notlimited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term“non-heteroaryl,” which is also included in the term “aryl,” defines agroup that contains an aromatic group that does not contain aheteroatom. The aryl group can be substituted or unsubstituted. The arylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiolas described herein. The term “biaryl” is a specific type of aryl groupand is included in the definition of “aryl.” Biaryl refers to two arylgroups that are bound together via a fused ring structure, as innaphthalene, or are attached via one or more carbon-carbon bonds, as inbiphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula NA¹A², where A¹ and A² can be, independently, hydrogen or alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein.

The term “alkylamino” as used herein is represented by the formula—NH(-alkyl) where alkyl is a described herein. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂ where alkyl is a described herein. Representative examplesinclude, but are not limited to, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by theformula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula—(A¹O(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula —(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The term “halide” as used herein refers to the halogens fluorine,chlorine, bromine, and iodine.

The term “heterocycle,” as used herein refers to single and multi-cyclicaromatic or non-aromatic ring systems in which at least one of the ringmembers is other than carbon. Heterocycle includes pyridinde,pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole,oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole,1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including,1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole,including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridine, pyridazine,pyrimidine, pyrazine, triazine, including 1,2,4-triazine and1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine,piperidine, piperazine, morpholine, azetidine, tetrahydropyran,tetrahydrofuran, dioxane, and the like.

The term “hydroxyl” as used herein is represented by the formula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” as used herein is represented by the formula —N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” as used herein is represented by the formula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A¹S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R¹,” “R²,” “R³,” “R^(n),” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e. further substituted orunsubstituted). The term “stable,” as used herein, refers to compoundsthat are not substantially altered when subjected to conditions to allowfor their production, detection, and, in certain aspects, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(o) ₂; —N(R^(∘))C(S)NR^(o)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(o) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(o)₂; —C(S)NR^(o) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(o) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(o) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(o) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(o) ₂; —P(O)₂R^(∘); —P(O)R^(o) ₂; —OP(O)R^(o)₂; —OP(O)(OR^(o) ₂; SiR^(o) ₃; —(C₁₋₄ straight orbranched)alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘)may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘)(or the ring formed by takingtwo independent occurrences of R^(∘)together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R⁵⁷⁴ , -(haloR⁵⁷⁴ ),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR⁵⁷⁴ , —(CH₂)₀₋₂CH(OR⁵⁷⁴ )₂; —O(haloR⁵⁷⁴ ), —CN,—N₃, —(CH₂)₀₋₂C(O)R⁵⁷⁴ , —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR⁵⁷⁴ ,—(CH₂)₀₋₂SR⁵⁷⁴ , —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR⁵⁷⁴ ,—(CH₂)₀₋₂NR⁵⁷⁴ ₂, —NO₂, —SiR⁵⁷⁴ ₃, —OSiR⁵⁷⁴ ₃, —C(O)SR⁵⁷⁴, —(C₁₋₄straight or branched alkylene)C(O)OR⁵⁷⁴, or —SSR⁵⁷⁴ wherein each R⁵⁷⁴ isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘)include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R⁵⁷⁴, -(haloR⁵⁷⁴), —OH, —OR⁵⁷⁴, —O(haloR⁵⁷⁴), —CN, —C(O)OH, —C(O)OR⁵⁷⁴,—NH₂, —NHR⁵⁷⁴, —NR⁵⁷⁴ ₂, or —NO₂, wherein each R⁵⁷⁴ is unsubstituted orwhere preceded by “halo” is substituted only with one or more halogens,and is independently C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R⁵⁷⁴, -(haloR⁵⁷⁴), —OH, —OR⁵⁷⁴, —O(haloR⁵⁷⁴), —CN, —C(O)OH,—C(O)OR⁵⁷⁴, —NH₂, —NHR⁵⁷⁴, —NR⁵⁷⁴ ₂, or —NO₂, wherein each R⁵⁷⁴ isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, brosylate, and halides.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitatation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has the structure

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5,6,7,8-tetrahydro-2-naphthyl radical.In some embodiments, an organic radical can contain 1-10 inorganicheteroatoms bound thereto or therein, including halogens, oxygen,sulfur, nitrogen, phosphorus, and the like. Examples of organic radicalsinclude but are not limited to an alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, mono-substituted amino, di-substituted amino,acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide,alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy,substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl,heteroaryl, heterocyclic, or substituted heterocyclic radicals, whereinthe terms are defined elsewhere herein. A few non-limiting examples oforganic radicals that include heteroatoms include alkoxy radicals,trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals andthe like.

“Inorganic radicals,” as the term is defined and used herein, contain nocarbon atoms and therefore comprise only atoms other than carbon.Inorganic radicals comprise bonded combinations of atoms selected fromhydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, andhalogens such as fluorine, chlorine, bromine, and iodine, which can bepresent individually or bonded together in their chemically stablecombinations. Inorganic radicals have 10 or fewer, or preferably one tosix or one to four inorganic atoms as listed above bonded together.Examples of inorganic radicals include, but not limited to, amino,hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonlyknown inorganic radicals. The inorganic radicals do not have bondedtherein the metallic elements of the periodic table (such as the alkalimetals, alkaline earth metals, transition metals, lanthanide metals, oractinide metals), although such metal ions can sometimes serve as apharmaceutically acceptable cation for anionic inorganic radicals suchas a sulfate, phosphate, or like anionic inorganic radical. Inorganicradicals do not comprise metalloids elements such as boron, aluminum,gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gaselements, unless otherwise specifically indicated elsewhere herein.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and l or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Inglod-Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labelled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl,respectively. Compounds further comprise prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of the present invention and prodrugsthereof can generally be prepared by carrying out the procedures below,by substituting a readily available isotopically labelled reagent for anon-isotopically labelled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvate orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et. al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. Unless stated to the contrary, theinvention includes all such possible tautomers.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, Rn is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), orSigma (St. Louis, Mo.) or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition); and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds can not be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. mGluR5 Negative Allosteric Modulators

In one aspect, the invention relates to compounds useful as negativeallosteric modulators of the metabotropic glutamate receptor subtype 5(mGluR5). Negative allosteric modulators are non-competitive antagonistsand can include a range of maximal antagonist activity from partialantagonists to inverse agonists. In one aspect, the present inventionrelates to compounds that allosterically modulate mGluR5 receptoractivity, affecting the sensitivity of mGluR5 receptors to agonistswithout acting as orthosteric agonists themselves. The compounds can, inone aspect, exhibit subtype selectivity. The compounds of the inventioncan be useful in the treatment neurological and psychiatric disordersassociated with glutamate dysfunction and other diseases in whichmetabotropic glutamate receptors are involved, as further describedherein. Generally, the disclosed compounds exhibit negative allostericmodulation of mGluR5 response to glutamate as a decrease in response tonon-maximal concentrations of glutamate in human embryonic kidney cellstransfected with rat mGluR5 in the presence of the compound, compared tothe response to glutamate in the absence of the compound. In furtheraspect, the human embryonic kidney cells are transfected with humanmGluR5. In yet a further aspect, human embryonic kidney cells aretransfected with mGluR5 of a mammal.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In one aspect, the invention relates to compounds, or pharmaceuticallyacceptable salts thereof, having a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein W is CR⁶ or N;wherein Z is CR^(6a) or N; provided that only one of W and Z is N;wherein R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; whereinR¹ is substituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁶, when present, is selected from hydrogen, halogen, CN, C3-C4cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl;wherein each of R^(6a) and R^(6b) is independently selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6haloalkoxy; wherein R^(6c) is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R⁷is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl,C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino; and wherein eachR⁹, when present, is independently halogen, C1-C6 alkyl, C1-C6haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, NO₂, CN, SO₂R⁸,or COR⁸; wherein the compound exhibits partial or total inhibition ofmGluR5 response to glutamate as a decrease in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith rat mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound.

In a further aspect, a compound has a structure selected from:

a. A Groups

In one aspect, A is CR² or N. In a further aspect, A is CH. In a yetfurther aspect, A is CH, and R⁴ and R⁵ are hydrogen. In a still furtheraspect, A is CH, and R³, R⁴, and R⁵ are all H. In an even furtheraspect, A is N. In a yet further aspect, A is N, and R⁴ and R⁵ arehydrogen. In a still further aspect, A is N and R³, R⁴, and R⁵ are allH.

b. L Groups

In one aspect, L is O or NR⁷. In a further aspect, L is O. In a yetfurther aspect, L is NH. In a still further aspect, L is NR⁷, wherein R⁷is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In an even further aspect,L is NR⁷, wherein R⁷ is methyl or ethyl. In a further aspect, L is NR⁷,wherein R⁷ is methyl. In a still further aspect, L is NR⁷, wherein R⁷ isethyl. In a yet further aspect, L is NR⁷, wherein R⁷ is hydrogen.

c. W Groups

In one aspect, W is CR⁶ or N, provided only one of W and Z is N. In afurther aspect, W is CR⁶, wherein R⁶ is selected from hydrogen, halogen,CN, C1-C6 alkyl, and C1-C6 haloalkyl, C3-C4 cycloalkyl, C3-C4halocycloalkyl. In a yet further aspect, W is N.

d. Z Groups

In one aspect, Z is CR^(6a) or N, provided only one of W and Z is N. Ina further aspect, Z is CR^(6a), wherein R^(6c) is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6haloalkoxy. In yet a further aspect, Z is N.

e. R¹ Groups

In one aspect, R¹ aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;wherein R¹ is substituted with 0-3 of R⁹. In a further aspect, R¹ isphenyl substituted with 0-3 of R⁹, and wherein R² is halogen, CN, alkyl,methyl. In a still further aspect, R¹ is phenyl substituted with 0-3 ofR⁹. In a yet further aspect, R¹ is phenyl substituted with 1-3 of R⁹. Inan even further aspect, R¹ is phenyl substituted with 1-2 of R⁹. In afurther aspect, R¹ is phenyl substituted with 1 of R⁹. In a stillfurther aspect, R¹ is phenyl substituted with 2 of R⁹. In a yet furtheraspect, R¹ is heterocyclic. In an even further aspect, R¹ is substitutedwith 0-3 of R⁹ and selected from C3-C8 cycloalkyl, C3-C8 cycloalkenyl,C6-C8 cycloalkynyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl,and C6-C8 heterocycloalkynyl. In a further aspect, R¹ is selected fromaryl and heteroaryl, each independently substituted with 0-3 of R⁹.

In a further aspect, R¹ is selected from acridine, phenyl, benzyl,benzisoxazole, benzo[c]thiophene, benzofuran, benzothiazole,benzothiophene, benzoxazole, cinnoline, furan, imidazole, indazole,isobenzofuran, isoindole, isoquinoline, isoxazole, naphthalene, oxazole,purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,quinazoline, quinoline, quinoxaline, thiazole, and thiophene. In a yetfurther aspect, R¹ is further substituted with 1-3 of R⁹.

f. R² Groups

In one aspect, R² is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl,C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl, alkylamino,dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸. In a further aspect, R² isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, and C1-C6 haloalkoxy. In a still further aspect, R² is hydrogen.In a yet further aspect, R² is halogen, C1-C6 alkyl, C1-C6 haloalkyl,C1-C6 alkoxy, or C1-C6 haloalkoxy.

g. R³ Groups

In one aspect, R³ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, and CN. In a further aspect, R³ is hydrogen. In a yet furtheraspect, R³ is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, andCN.

In a further aspect, R³ is selected from methyl, ethyl, n-propyl,i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, cyclobutyl, n-pentyl,i-pentyl, s-pentyl, neopentyl, cyclopentyl, n-hexyl, i-hexyl, s-hexyl,dimethylbutyl, and cyclohexyl.

h. R⁴ Groups

In one aspect, R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸. In a further aspect, R⁴ ishydrogen. In a still further aspect, R⁴ is halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino, alkylamino,dialkylamino, CN, SO₂R⁸, or COR⁸. In a yet further aspect, R⁴ ishydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6haloalkoxy. In an even further aspect, R⁴ is halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. In a further aspect, R⁴ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN,SO₂R⁸, and COR⁸.

In a further aspect, R⁴ is selected from methyl, ethyl, n-propyl,i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, cyclobutyl, n-pentyl,i-pentyl, s-pentyl, neopentyl, cyclopentyl, n-hexyl, i-hexyl, s-hexyl,dimethylbutyl, and cyclohexyl.

i. R⁵ Groups

In one aspect, R⁵ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, CN, SO₂R⁸, and COR⁸. In a further aspect, R⁵ is hydrogen. Ina still further aspect, R⁵ is halogen, C1-C6 alkyl, C1-C6 haloalkyl,C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino, alkylamino,dialkylamino, CN, SO₂R⁸, or COR⁸. In a yet further aspect, R⁵ ishydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In an even furtheraspect, R⁵ is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, orC1-C6 haloalkoxy. In a further aspect, R⁵ is selected from hydrogen,halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR^(S). In astill further aspect, R⁵ is hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl or CN.

j. R⁶ Groups

In one aspect, R⁶ is, when present, is selected from hydrogen, halogen,CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl, and C3-C4cyclohaloalkyl. In a further aspect, R⁶ is hydrogen. In a still furtheraspect, R⁶ is selected from halogen, CN, C1-C6 alkyl, and C1-C6haloalkyl. In a yet further aspect, R⁶ is selected from hydrogen,halogen, and CN. In an even further aspect, R⁶ is selected from C1-C6alkyl and C1-C6 haloalkyl.

k. R^(6a) and R^(6b) Groups

In one aspect, each R^(6a) and R^(6b) is independently selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6haloalkoxy. In a further aspect, R^(6a) is hydrogen. In a furtheraspect, R^(6a) is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl,C1-C6 alkoxy, and C1-C6 haloalkoxy. In a further aspect, R^(6a) isselected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 haloalkyl. In afurther aspect, R^(6b) is hydrogen. In a further aspect, R^(6b) isselected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, andC1-C6 haloalkoxy. In a further aspect, R^(6b) is selected from hydrogen,halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

l. R^(6c) Groups

In one aspect, R^(6a) is independently selected from hydrogen, halogen,C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. In afurther aspect, R^(6c) is hydrogen. In a further aspect, R^(6c) isselected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, andC1-C6 haloalkoxy. In a further aspect, R^(6c) is selected from hydrogen,halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

m. R⁷ Groups

In one aspect, R⁷ is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In afurther aspect, R⁷ is hydrogen. In a yet further aspect, R⁷ is selectedfrom C1-C6 alkyl and C1-C6 haloalkyl. In a further aspect, R⁷ is ethylor methyl. In a yet further aspect, R⁷ is methyl. In a still furtheraspect, R⁷ is ethyl.

In a further aspect, R⁷ is selected from methyl, ethyl, n-propyl,i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, cyclobutyl, n-pentyl,i-pentyl, s-pentyl, neopentyl, cyclopentyl, n-hexyl, i-hexyl, s-hexyl,dimethylbutyl, and cyclohexyl.

n. R⁸ Groups

In one aspect, R⁸ is C1-C6 alkyl, C1-C6 cycloalkyl, amino, alkylamino,or dialkylamino. In a further aspect, R⁸ is selected from amino,alkylamino, and dialkylamino. In a still further aspect, R⁸ is selectedfrom C1-C6 alkyl and C1-C6 cycloalkyl. For example, R⁸ can be methyl,ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl,cyclobutyl, n-pentyl, i-pentyl, s-pentyl, neopentyl, cyclopentyl,n-hexyl, i-hexyl, s-hexyl, dimethylbutyl, or cyclohexyl.

o. R⁹ Groups

In one aspect, each R⁹, when present, is independently halogen, C1-C6alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6alkoxy, C1-C6 haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino,NO₂, CN, SO₂R⁸, or COR⁸. In a further aspect, R⁹ is present and each R⁹is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl,C1-C6 alkoxy, C1-C6 haloalkoxy, CN, hydroxyl, amino, alkylamino,dialkylamino, NO₂, SO₂R⁸, and COR⁸. In a still further aspect, R⁹ ispresent and each R⁹ is independently selected from halogen, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, hydroxyl, amino,alkylamino, and dialkylamino. In a yet further aspect, R⁹ is present andeach R⁹ is independently selected from halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and CN.

It is contemplated that the disclosed compounds can be used inconnection with the disclosed methods, compositions, products, uses, andkits.

2. Example Structures

In one aspect, a compound can be present as:

In a further aspect, a compound can be present as:

In a yet further aspect, a compound can be present as:

In a still further aspect, a compound can be present as:

In an even further aspect, a compound can be present as:

In a further aspect, a compound can be present as:

In a yet further aspect, a compound can be present as:

In a still further aspect, a compound can be present as:

In an even further aspect, a compound can be present as:

In a further aspect, a compound can be present as:

In a yet further aspect, a compound can be present as:

In yet a further aspect, the compound exhibits negative allostericmodulation of mGluR5 response to glutamate as a decrease in response tonon-maximal concentrations of glutamate in human embryonic kidney cellstransfected with rat mGluR5 in the presence of the compound, compared tothe response to glutamate in the absence of the compound. In a furtheraspect, human embryonic kidney cells are transfected with human mGluR5.In yet a further aspect, human embryonic kidney cells are transfectedwith mammalian mGluR5. In a further aspect, the compound exhibitspartial or total inhibition of mGluR5 in response to glutamate as adecrease in response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with human, rat or mammalian mGluR5in the presence of the compound, compared to the response to glutamatein the absence of the compound. In yet a further aspect, the compoundexhibits negative allosteric modulation of mGluR5 after contacting acell expressing mGluR5. In a further aspect, the compound producedexhibits partial or total inhibition of mGluR5 after contacting a cellexpressing mGluR5.

It is contemplated that one or more example structures can be optionallyomitted from the disclosed invention.

3. Atropisomeric Forms

Atropisomers are stereoisomers resulting from hindered rotation aboutsingle bonds where the steric strain barrier to rotation is high enoughto allow for the isolation of the conformers. Atropisomers display axialchirality, but differ from other chiral compounds in that they can beequilibrated thermally, whereas in the other forms of chiralityisomerization is usually only possible chemically. In certains aspects,the disclosed compounds can be provided as atropisomeric compounds. Forexample, disclosed compounds can be provided as single atropisomers oras a mixture of atropisomers.

It is contemplated that one atropisomer can exhibit greater negativeallosteric modulation of mGluR5 response to glutamate than another,otherwise structurally identical, atropisomer. Thus, individualatropisomers of disclosed compounds can be isolated and used indisclosed methods. Separation of atropisomers can be achieved by chiralresolution methods such as selective crystallization.

In an atropo-enantioselective or atropselective synthesis, oneatropisomer is formed at the expense of the other. Thus, it is alsocontemplated that a specific atropisomer can be preferentially prepared:atroposelective synthesis can be carried out by use of chiralauxiliaries or by approaches based on thermodynamic equilibration whenan isomerization reaction favors one atropisomer over the other.

4. Negative Allosteric Modulation of mGluR5 Response

In one aspect, the compounds exhibit negative allosteric modulation ofmGluR5 response to glutamate as a decrease in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith rat mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound. In a furtheraspect, the compound exhibits partial inhibition of mGluR5 response. Ina further aspect, the compound exhibits total inhibition of mGluR5response. In a further aspect, the compound exhibits negative allostericmodulation with an IC₅₀ of less than about 30×10⁻⁶. In a further aspect,the compound exhibits negative allosteric modulation with an IC₅₀ ofless than about 10×10⁻⁶. In a further aspect, the compound exhibitspartial or total inhibition with an IC₅₀ of less than about 1.0×10⁻⁶, ofless than about 1.0×10⁻⁷, of less than about 1.0×10⁻⁸ or of less thanabout 1.0×10⁻⁹. In further aspect, the human embryonic kidney cells aretransfected with human mGluR5. In yet a further aspect, human embryonickidney cells are transfected with mGluR5 of a mammal.

C. Metabotropic Glutamate Receptor Activity

The utility of the compounds in accordance with the present invention asnegative allosteric modulators of metabotropic glutamate receptoractivity, in particular mGluR5 activity, can be demonstrated bymethodology known in the art. Human embryonic kidney (HEK) cellstransfected with rat or human mGluR5 were plated in clear bottom assayplates for assay in a Functional Drug Screening System (FDSS). The cellswere loaded with a Ca2+-sensitive fluorescent dye (e.g., Fluo-4), andthe plates were washed and placed in the FDSS instrument. Test compoundwas applied to cells 3 seconds after baseline readings were taken. Cellswere incubated with the test compounds for 140 seconds and thenstimulated with an EC₂₀ concentration of an mGluR5 agonist (e.g.,glutamate, 3,5-dihydroxyphenylglycine, or quisqualate); 60-80 secondslater an EC₈₀ concentration of agonist was added and readings taken foran additional 40 seconds. Data were collected at 1 Hz. Negativeallosteric modulation of the agonist response of mGluR5 by the compoundsin the present invention was observed as a decrease in response tonon-maximal concentrations of agonist (here, glutamate) in the presenceof compound compared to the response to agonist in the absence ofcompound. Concentration response curves were generated using a fourparameter logistical equation.

The above described assay was operated in two modes. In the first mode(utilizing a triple add protocol), a range of concentrations of thepresent compounds were added to cells, followed by two single fixedconcentrations of agonist (EC₂₀ followed by EC₈₀). If a compound actedas a potentiator, an EC₅₀ value for potentiation of the EC₂₀ responseand a maximum extent of potentiation by the compound at thisconcentration of agonist was determined by non-linear curve fitting. Ifa compound acted as an antagonist, an IC₅₀ value for antagonism of theEC₈₀ response and a maximum extent of antagonism by the compound at thisconcentration of agonist was determined by non-linear curve fitting. Inthe second mode (utilizing a double add protocol), several fixedconcentrations of the present compounds were added to various wells on aplate, followed by a range of concentrations of agonist for eachconcentration of present compound; the EC₅₀ values for the agonist ateach concentration of compound were determined by nonlinear curvefitting. A decrease in the EC₅₀ value of the agonist with increasingconcentrations of the present compounds (a leftward shift of the agonistconcentration-response curve) is an indication of the degree of mGluR5positive allosteric modulation at a given concentration of the presentcompound. An increase in the EC₅₀ value of the agonist with increasingconcentrations of the present compounds (a rightward shift of theagonist concentration response curve) is an indication of the degree ofmGluR5 antagonism at a given concentration of the present compound. Thesecond mode also indicates whether the present compounds also affect themaximum response to mGluR5 to agonists. Exemplary data are provided inTables 1 and 2 below.

In particular, the disclosed compounds had activity in modulating themGluR5 receptor in the aforementioned assays, generally with an IC50 formodulation of less than about 30 μM. Preferred compounds within thepresent invention had activity in modulating the mGluR5 receptor with anIC50 for negative allosteric modulation of less than about 500 nM.Preferred compounds reduced the response to an EC80 concentration ofglutamate to less than 50% of the maximal response and also induced arightward and downward shift of the glutamate concentration responsecurve. These compounds are negative allosteric modulators of human andrat mGluR5 and were selective for mGluR5 compared to the other sixsubtypes of metabotropic glutamate receptors.

D. Methods of Making the Compounds

In one aspect, the invention relates to methods of making compoundsuseful as negative allosteric modulators of the metabotropic glutamatereceptor subtype 5 (mGluR5), which can be useful in the treatmentneurological and psychiatric disorders associated with glutamatedysfunction and other diseases in which metabotropic glutamate receptorsare involved.

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

The disclosed compounds can be prepared by various routes. In certainspecific examples, the disclosed compounds can be prepared by Routes Ithrough VI, as described and exemplified below.

In a further aspect, a compound comprises the product of the disclosedmethods. In a still further aspect, the invention comprises apharmaceutical composition comprising a therapeutically effective amountof the product of the disclosed methods and a pharmaceuticallyacceptable carrier. In a still further aspect, the invention comprises amethod for manufacturing a medicament comprising combining at least onecompound of any of disclosed compounds or at least one product of thedisclosed methods with a pharmaceutically acceptable carrier or diluent.

For example, in one aspect, a method of making a compound comprising thestep of reacting a compound having a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein R² is hydrogen,halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy,amino, hydroxyl, alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸;wherein R³ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, and CN; wherein R⁴ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl,amino, alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the provisothat when A is N, then R⁴ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁷ is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and wherein R⁸is C1-C6 alkyl, C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino;with a second compound having a structure represented by a formula:

wherein X is a leaving group; wherein W is CR⁶ or N; wherein Z isCR^(6a) or N; provided that only one of W and Z is N; wherein each ofR^(6a) and R^(6b) is independently selected from hydrogen, halogen,C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; andwherein R^(6c) is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, thereby forming a producthaving a structure represented by a formula:

In a further aspect, X is halogen. In a yet further aspect, wherein X isF. In a still further aspect, L is O.

In a further aspect, the step of providing a compound comprises the stepof hydrolyzing the product to form a carboxylate having a structurerepresented by a formula:

In a further aspect, the method of making a compound further comprisesthe step of reacting the carboxylate with an alcohol to form an ester.

In a further aspect, the method of making a compound further comprisesthe step of reacting the ester with R¹NH₂ to form an amide having astructure represented by a formula:

wherein R¹ is selected from aryl, heteroaryl, cycloalkyl, andheterocycloalkyl; and wherein R¹ is substituted with 0-3 of R⁹.

In a further aspect, the method of making a compound comprises the stepof reacting the carboxylate with R¹NH₂ to form an amide having astructure represented by a formula:

wherein R¹ is selected from aryl, heteroaryl, cycloalkyl, andheterocycloalkyl; and wherein R¹ is substituted with 0-3 of R⁹.

In a further aspect, R¹ is selected from aryl and heteroaryl, eachindependently substituted with 0-3 of R⁹. In a yet further aspect,R^(6a), R^(6b), and R^(6c) is hydrogen. In a still further aspect, R³,R⁴, and R⁵ are all hydrogen.

In one aspect, a method of making a compound comprising the step ofreacting a compound having a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein R² is hydrogen,halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy,amino, hydroxyl, alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸;wherein R³ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, and CN; wherein R⁴ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl,amino, alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the provisothat when A is N, then R⁴ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁷ is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and wherein R⁸is C1-C6 alkyl, C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino,with a second compound having a structure represented by a formula:

wherein X¹ and X² are independently selected from leaving groups;wherein W is CR⁶ or N; wherein Z is CR^(6a) or N; provided that only oneof W and Z is N; wherein R⁶, when present, is selected from hydrogen,halogen, CN, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, andC1-C6 haloalkyl; wherein each of R^(6a) and R^(6b) is independentlyselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, and C1-C6 haloalkoxy; and wherein R^(6c) is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6haloalkoxy, thereby forming a product having a structure represented bya formula:

In a further aspect, X¹ is halogen. In a still further aspect, X¹ isfluoro. In a yet further aspect, X² is halogen. In an even furtheraspect, X² is bromo or iodo. In a further aspect, X¹ is fluoro, andwherein X² is bromo.

In a further aspect, the method of making a compound further comprisesthe step of performing a cyanation reaction to provide a compound havinga structure represented by a formula:

In a further aspect, the method of making further comprises the step ofhydrolyzing the nitrile to form a carboxylate having a structurerepresented by a formula:

In a yet further aspect, the method of making further comprises the stepof reacting the carboxylate with an alcohol to form an ester. In a yetfurther aspect, the ester has a structure represented by a formula:

In a further aspect, the method of making further comprises the step ofreacting the ester with R¹NH₂ to form an amide having a structurerepresented by a formula:

wherein R¹ is selected from aryl, heteroaryl, cycloalkyl, andheterocycloalkyl; and wherein R¹ is substituted with 0-3 of R⁹.

In a further aspect, the method of making further comprises the step ofreacting the carboxylate with R¹NH₂ to form an amide having a structurerepresented by a formula:

wherein R¹ is selected from aryl, heteroaryl, cycloalkyl, andheterocycloalkyl; and wherein R¹ is substituted with 0-3 of R⁹.

I a further aspect, the method of making a compound comprises the amideformed, wherein R¹ is selected from aryl and heteroaryl, eachindependently substituted with 0-3 of R⁹.

In a further aspect, each of R^(6a), R^(6b), and R^(6c) is hydrogen. Ina yet further aspect, R³, R⁴, and R⁵ are all hydrogen.

In a further aspect, a compound comprises the product of the disclosedmethods. In a still further aspect, the invention comprises apharmaceutical composition comprising a therapeutically effective amountof the product of the disclosed methods and a pharmaceuticallyacceptable carrier. In a still further aspect, the invention comprises amethod for manufacturing a medicament comprising combining at least onecompound of any of disclosed compounds or at least one product of thedisclosed methods with a pharmaceutically acceptable carrier or diluent.

1. Route I

In one aspect, substituted heteroarylamide analogs can be prepared asshown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, Route I begins with a substituted or unsubstitutedcommercially available 2-cyano-4-halopyridine or a substituted orunsubstituted commercially available 3-cyano-5-halopyridine. Reactionwith a heteroaryl alcohol under basic conditions results in S_(N)Ardisplacement of the aryl halide and yields a biaryl ether. The resultingintermediate nitrile can be treated with aqueous hydroxide to providethe heteroaryl carboxylic acid. Coupling of the carboxylic acid with aprimary amine can yield the amide product. Such coupling reactions aregenerally well known. For example, carboxylic acids can be treated withactivating reagents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),dicyclo-hexylcarbodiimide (DCC), 1,1′-Carbonyldiimidazole (CDI),N,N′-diisopropyl-carbodiimide (DIP),2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluoro-phosphate methanaminium (HATU),benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexa-fluorophosphate (BOP), hydroxybenzotriazole (HOBt), andN-methylmorpholine (NMM), including mixtures thereof, and then reactedwith the amine. Functional group transformation of the remainingsubstituents can yield further analogs.

Thus, in one aspect, the invention relates to a method of making acompound comprising the step of reacting a compound having a structurerepresented by a formula:

wherein X is a leaving group; wherein W is CR⁶ or N; wherein Z isCR^(6a) or N; provided that only one of W and Z is N; wherein R⁶ isselected from hydrogen, halogen, CN, C1-C6 alkyl, and C1-C6 haloalkyl,C3-C4 cycloalkyl, C3-C4 halocycloalkyl; wherein R^(6a) and R^(6b) isindependently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R^(6c), isindependently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; with a second compoundhaving a structure represented by a formula:

wherein A is CR² or N; wherein R² is hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl,C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino, alkylamino,dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso that when A is N,then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁸ is C1-C6 alkyl, C1-C6cycloalkyl, amino, alkylamino, or dialkylamino; and, wherein R⁵ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN,SO₂R⁸, and COR⁸; under basic conditions, thereby forming an ether.

In a further aspect, the compound produced has a structure representedby a formula:

In a further aspect, the method further comprises the step of reactingthe nitrile intermediate with aqueous hydroxide, thereby forming acarboxylic acid, having a structure represented by a formula:

In a further aspect, the method further comprises the step of couplingwith a primary amine, thereby forming an amide having a structurerepresented by a formula:

wherein R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; whereinR¹ is substituted with 0-3 of R⁹; and, wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸.

In a further aspect, the compound produced exhibits negative allostericmodulation of mGluR5 response to glutamate as a decrease in response tonon-maximal concentrations of glutamate in human embryonic kidney cellstransfected with rat mGluR5 in the presence of the compound, compared tothe response to glutamate in the absence of the compound. In a furtheraspect, human embryonic kidney cells are transfected with human mGluR5.In yet a further aspect, human embryonic kidney cells are transfectedwith mammalian mGluR5. In a further aspect, the compound producedexhibits partial or total inhibition of mGluR5 in response to glutamateas a decrease in response to non-maximal concentrations of glutamate inhuman embryonic kidney cells transfected with human, rat or mammalianmGluR5 in the presence of the compound, compared to the response toglutamate in the absence of the compound. In yet a further aspect, thecompound produced exhibits negative allosteric modulation of mGluR5after contacting a cell expressing mGluR5. In a further aspect, thecompound produced exhibits partial or total inhibition of mGluR5 aftercontacting a cell expressing mGluR5.

2. Route II

In one aspect, substituted heteroarylamide analogs can be prepared asshown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, Route II begins with a substituted or unsubstitutedcommercially available 2,4-dihalopyridine or a substituted orunsubstituted commercially available 3,5-dihalopyridine. Reaction with aheteroaryl alcohol under basic conditions results in S_(N)Ardisplacement of one of the aryl halides and yields a biaryl ether. Apalladium catalyzed cyanation reaction can be used to generate the arylnitrile compound from the heteroaryl halide intermediate. It will beappreciated that a variety of palladium catalysts, ligands, and cyanidesources may be suitable for this coupling reaction (see Synthetic Comm.2007, 37, 431-438 and references therein). Examples of potentiallyuseful palladium catalysts for this coupling include but are not limitedto tris(di-benzylideneacetone)-dipalladium(0), palladium acetate, andtetrakis(triphenylphosphine)-palladium. Examples of potentially usefulphosphine ligands for this coupling include but are not limited totriphenylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, and1,4-bis(diphenyl-phosphino)butane. Examples of potentially usefulcyanide sources for this coupling include but are not limited to zinccyanide, potassium ferricyanide, trimethylsilyl cyanide, and potassiumcyanide. The resulting intermediate nitrile can be treated with aqueoushydroxide to provide the aryl carboxylic acid. Coupling of thecarboxylic acid with a primary amine as described in Route 1 can yieldthe amide product.

Thus, in one aspect, the invention relates to a method of making acompound comprising the step of reacting a compound having a structurerepresented by a formula:

X¹ and X² are independently selected from leaving groups; wherein W isCR⁶ or N; wherein Z is CR^(6a) or N; provided that only one of W and Zis N; wherein R² is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl,C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl, alkylamino,dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R⁶, when present, isselected from hydrogen, halogen, CN, C1-C6 alkyl, and C1-C6 haloalkyl,C3-C4 cycloalkyl, C3-C4 halocycloalkyl, wherein R^(6a) and R^(6b) isindependently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R^(6c), isindependently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; with a second compoundhaving a structure represented by a formula:

wherein A is CR² or N; wherein R³ is selected from hydrogen, halogen,C1-C6 alkyl, C1-C6 haloalkyl, and CN; R⁴ is selected from hydrogen,halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, CN, SO₂R⁸, andCOR⁸, with the proviso that when A is N, then R⁴ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁸ is C1-C6 alkyl, C1-C6 cycloalkyl, amino, alkylamino, ordialkylamino; and, wherein R⁵ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; under basic conditions,thereby forming an ether.

In a further aspect, the compound produced has a structure representedby a formula:

In a further aspect, the method further comprises the step of reactingthe heteroaryl halide intermediate in a palladium catalyzed cyanationreaction in order to generate the aryl nitrile compound, having astructure represented by a formula:

In a further aspect, the method further comprises the step of reactingthe nitrile intermediate with aqueous hydroxide, thereby forming acarboxylic acid, having a structure represented by a formula:

In a further aspect, the method further comprises the step of couplingwith a primary amine, thereby forming an amide having a structurerepresented by a formula:

wherein R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; whereinR¹ is substituted with 0-3 of R⁹; and, wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR^(S).

In a further aspect, the compound produced exhibits negative allostericmodulation of mGluR5 response to glutamate as a decrease in response tonon-maximal concentrations of glutamate in human embryonic kidney cellstransfected with rat mGluR5 in the presence of the compound, compared tothe response to glutamate in the absence of the compound. In a furtheraspect, human embryonic kidney cells are transfected with human mGluR5.In yet a further aspect, human embryonic kidney cells are transfectedwith mammalian mGluR5. In a further aspect, the compound producedexhibits partial or total inhibition of mGluR5 in response to glutamateas a decrease in response to non-maximal concentrations of glutamate inhuman embryonic kidney cells transfected with human, rat or mammalianmGluR5 in the presence of the compound, compared to the response toglutamate in the absence of the compound. In yet a further aspect, thecompound produced exhibits negative allosteric modulation of mGluR5after contacting a cell expressing mGluR5. In a further aspect, thecompound produced exhibits partial or total inhibition of mGluR5 aftercontacting a cell expressing mGluR5.

3. Route III

In one aspect, substituted heteroarylamide analogs can be prepared asshown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, Route III begins with a substituted or unsubstitutedpyridyl carboxylic acid that can be prepared according to methodsoutlined herein. Reaction with an alkylating agent under basicconditions or a Mitsunobu reaction with a primary alcohol can be used toprovide the ester. It will be appreciated that other well known methodsfor preparing the ester may be employed. The ester can be treated with aprimary amine and a suitable base to afford the amide product. It willbe appreciated that a number of bases may be suitable for this type oftransformation. Examples of potentially suitable bases include but arenot limited to potassium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, potassium hydride, and sodium hydride.Functional group transformation of the remaining substituents can yieldfurther analogs.

Thus, in one aspect, the invention relates to a method of making acompound comprising the step of reacting a compound having a structurerepresented by a formula:

wherein L is O or NR⁷; wherein W is CR⁶ or N; wherein Z is CR^(6a) or N;provided that only one of W and Z is N; wherein R² is hydrogen, halogen,C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino,hydroxyl, alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R⁶,when present, is selected from hydrogen, halogen, CN, C1-C6 alkyl, andC1-C6 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, wherein R^(6a)and R^(6b) is independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; whereinR^(6c), is independently selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; with a secondcompound having a structure represented by a formula: wherein A is CR²or N; wherein R³ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, and CN; wherein R⁴ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl,amino, alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the provisothat when A is N, then R⁴ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁷ is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein R⁸ isC1-C6 alkyl, C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino; withR¹⁰X, wherein R¹⁰ is optionally substituted alkyl; and wherein X is aleaving group or a hydroxyl.

In a further aspect, the compound produced has a structure representedby a formula:

In a further aspect, the method further comprises the step of reactingthe ester intermediate with a primary amine and a suitable base, therebyforming an amide having a structure represented by a formula:

wherein R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; whereinR¹ is substituted with 0-3 of R⁹; and, wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸.

In a further aspect, the compound produced exhibits negative allostericmodulation of mGluR5 response to glutamate as a decrease in response tonon-maximal concentrations of glutamate in human embryonic kidney cellstransfected with rat mGluR5 in the presence of the compound, compared tothe response to glutamate in the absence of the compound. In a furtheraspect, human embryonic kidney cells are transfected with human mGluR5.In yet a further aspect, human embryonic kidney cells are transfectedwith mammalian mGluR5. In a further aspect, the compound producedexhibits partial or total inhibition of mGluR5 in response to glutamateas a decrease in response to non-maximal concentrations of glutamate inhuman embryonic kidney cells transfected with human, rat or mammalianmGluR5 in the presence of the compound, compared to the response toglutamate in the absence of the compound. In yet a further aspect, thecompound produced exhibits negative allosteric modulation of mGluR5after contacting a cell expressing mGluR5. In a further aspect, thecompound produced exhibits partial or total inhibition of mGluR5 aftercontacting a cell expressing mGluR5.

4. Route IV

In one aspect, substituted heteroarylamide analogs can be prepared asshown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, Route IV begins with a substituted or unsubstitutedcommercially available 2-cyano-4-halopyridine or a substituted orunsubstituted commercially available 3-cyano-5-halopyridine.Alternatively, Route IV begins with a substituted or unsubstituted2-cyanopyridin-4-yl sulfonate or a substituted or unsubstitutedcommercially available 5-cyanopyridin-3-yl sulfonate. Such sulfonatecompounds are either commercially available or readily prepared by oneskilled in the art. Reaction proceeds with a substituted orunsubstituted 3-aminopyridine or a substituted or unsubstituted5-aminopyrimidine using a palladium catalyzed coupling in order to linkthe two groups via a secondary amine. It will be appreciated that avariety of palladium catalysts, phosphine ligands, and bases may besuitable for the palladium catalyzed coupling reaction (see NatureProtocols 2007, 2, 2881 and references therein). Examples of potentiallyuseful palladium catalysts for this coupling include but are not limitedto tris(dibenzylidene-acetone)dipalladium(0), palladium acetate, andtetrakis(triphenylphosphine)palladium. Examples of potentially usefulphosphine ligands for this coupling include but are not limited totert-butyl XPhos, XPhos, XANTPHOS, and BINAP. Examples of potentiallyuseful bases for this coupling include but are not limited to sodiumtert-butoxide, cesium carbonate, and potassium phosphate. Following thepalladium coupling, the secondary amine can be reacted with an alkylhalide or alkyl group with another suitable leaving group under basicconditions to produce a tertiary amine. It will be appreciated thatshould the secondary rather than tertiary amine target be of interestthat the aforementioned step would be skipped. The resultingintermediate nitrile can be treated with aqueous hydroxide to providethe aryl carboxylic acid. Coupling of the carboxylic acid with aheteroaryl primary amine as described in Route 1 can yield the amideproduct. Functional group transformation of the remaining substituentscan yield further analogs.

Thus, in one aspect, the invention relates to a method of making acompound comprising the step of reacting a compound having a structurerepresented by a formula:

wherein X is a leaving group; wherein W is CR⁶ or N; wherein Z isCR^(6a) or N; provided that only one of W and Z is N; wherein R⁶, whenpresent, is selected from hydrogen, halogen, CN, C1-C6 alkyl, and C1-C6haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, wherein each ofR^(6a) and R^(6b) is independently selected from hydrogen, halogen,C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;wherein R^(6c), is independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; with asecond compound having a structure represented by a formula:

wherein A is CR² or N; wherein R³ is selected from hydrogen, halogen,C1-C6 alkyl, C1-C6 haloalkyl, and CN; wherein R² is hydrogen, halogen,C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino,hydroxyl, alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; R⁴ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino,CN, SO₂R⁸, and COR⁸, with the proviso that when A is N, then R⁴ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN,SO₂R⁸, and COR⁸; and, wherein R⁵ is selected from hydrogen, halogen,C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁸ is C1-C6alkyl, C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino; under basicconditions, thereby forming an ether. under basic conditions, therebyforming a biaryl amine. In a further aspect, the leaving group is Cl,Br, I, or OSO₂R¹¹, wherein R¹¹ is alkyl, haloalkyl, or aryl.

In a further aspect, the compound produced has a structure representedby a formula:

In a further aspect, the method further comprises reaction with R⁷X,wherein, in a specific aspect, R⁷ is optionally substituted alkyl orhaloalkyl; and wherein X is a leaving group.

In a further aspect, the compound produced has a structure representedby a formula:

In a further aspect, the method further comprises the step of reactingthe nitrile intermediate with aqueous hydroxide, thereby forming acarboxylic acid, having a structure represented by a formula:

In a further aspect, the method further comprises the step of couplingwith a primary amine, thereby forming an amide having a structurerepresented by a formula:

wherein R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; whereinR¹ is substituted with 0-3 of R⁹; and, wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸.

In a further aspect, the compound produced exhibits negative allostericmodulation of mGluR5 response to glutamate as a decrease in response tonon-maximal concentrations of glutamate in human embryonic kidney cellstransfected with rat mGluR5 in the presence of the compound, compared tothe response to glutamate in the absence of the compound. In a furtheraspect, human embryonic kidney cells are transfected with human mGluR5.In yet a further aspect, human embryonic kidney cells are transfectedwith mammalian mGluR5. In a further aspect, the compound producedexhibits partial or total inhibition of mGluR5 in response to glutamateas a decrease in response to non-maximal concentrations of glutamate inhuman embryonic kidney cells transfected with human, rat or mammalianmGluR5 in the presence of the compound, compared to the response toglutamate in the absence of the compound. In yet a further aspect, thecompound produced exhibits negative allosteric modulation of mGluR5after contacting a cell expressing mGluR5. In a further aspect, thecompound produced exhibits partial or total inhibition of mGluR5 aftercontacting a cell expressing mGluR5.

It is contemplated that each disclosed methods can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed methods can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

Table 1 below lists specific compounds as well as a preferred route forits synthesis, experimentally determined molecular mass, and mGluR5activity determined in a cell-based assay. The mGluR5 activity wasdetermined using the metabotropic glutamate receptor activity assays inhuman embryonic kidney cells as described herein, wherein the humanembryonic kidney cells were transfected with rat mGluR5. The mGluR5activity data for some compounds are shown as the average of at leastthree experiments with the standard error in these cases. If no error isindicated for the mGluR5 activity, the values given represent theresults from a single experiment or the average of two experiments. Thecompounds in Table 1 were synthesized with methods identical oranalogous to those shown herein. The requisite starting materials werecommercially available, described in the literature, or readilysynthesized by one skilled in the art of organic synthesis.

TABLE 1 mGluR5 Synthetic IC₅₀ Route Structure (nM) M + 1 Reference

3460 292.2 I

358 ± 111 326.1 I

4860 360.2 I

>30,000 328.2 I

4050 296.2 I

2890 310.2 I

38 ± 7  307.2 I

164 ± 20  311.2 I

 510 306.2 I

85± 14 313.1 I

>30,000 360.1 I

>30,000 360.1 I

8990 299.1 I

3580 313.1 I

1920 327.0 I

1030 327.0 I

68 ± 11 293.2 I

 226 321.2 I

>30,000 311.2 I

1380 307.2 I

>30,000 297.2 I

 379 323.2 I

4690 294.1 I

>30,000 314.1 I

>10,000 331.1 II

>10,000 367.0 II

>10,000 293.1 II

6600 313.1 II

2640 324.0 I

181 ± 9  314.1 I

1110 367.0 I

2610 300.0 I

5590 312.1 IV

2690 326.1 IV

1930 327.2 IV

>30,000 325.1 IV

8350 325.1 IV

>30,000 270.1 I

>30,000 284.2 I

>30,000 298.1 I

>10,000 312.2 I

>10,000 300.1 I

>10,000 307.1 IV

5310 321.1 IV

>10,000 341.1 IV

>30,000 314.1 I

 114 294.1 I

 56 308.2 I or III

 389 312.1 I

>30,000 312.0 I

>30,000 330.1 I

 154 328.0 I

2470 328.1 I

>30,000 313.1 I

>30,000 301.1 I

2320 332.1 I

 216 312.1 I or III

>10,000 326.1 I

 128 312.1 I

 981 332.1 I

>30,000 322.1 I

>10,000 328.1 I

>30,000 309.1 I

>10,000 324.1 I

1220 308.2 I

6770 368.0 I

>30,000 370.2 I

>30,000 350.2 I

7050 350.1 I

>30,000 357.1 I

>30,000 392.0 I

>10,000 372.0 I

>10,000 344.1 I

>10,000 362.1 I

2140 324.2 I

>10,000 362.0 I

 746 326.1 I

Table 2 below lists representative compounds and the activity of eachmeasured in human embryonic kidney cells expressing, as indicated,either the human mGluR5 or the rat mGluR5. The mGluR5 activity wasdetermined using the metabotropic glutamate receptor activity assays inhuman embryonic kidney cells as described herein. The mGluR5 activitydata for some compounds are shown as the average of at least threeexperiments with the standard error in these cases. If no error isindicated for the mGluR5 activity, the values given represent theresults from a single experiment or the average of two experiments. Thecompounds in Table 2 were synthesized with methods identical oranalogous to those shown herein. The requisite starting materials werecommercially available, described in the literature, or readilysynthesized by one skilled in the art of organic synthesis.

TABLE 2 rat mGluR5 human mGluR5 IC₅₀ IC₅₀ Structure (nM) (nM)

358 ± 111  390

85 ± 14  101

6600 2160

181 ± 9   65

1930 1900

5310 2150

 114  84

 56  47

 389  364

 216  201

 128  161

 154  245

>30,000 >30,000

 981  943

E. Pharmaceutical Compositions

In one aspect, the invention relates to pharmaceutical compositionscomprising the disclosed compounds. That is, a pharmaceuticalcomposition can be provided comprising a therapeutically effectiveamount of at least one disclosed compound or at least one product of adisclosed method and a pharmaceutically acceptable carrier.

In certain aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases oracids. When the compound of the present invention is acidic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic bases, including inorganic bases and organic bases.Salts derived from such inorganic bases include aluminum, ammonium,calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium,manganese (-ic and -ous), potassium, sodium, zinc and the like salts.Particularly preferred are the ammonium, calcium, magnesium, potassiumand sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, as well as cyclic amines and substituted amines such asnaturally occurring and synthesized substituted amines. Otherpharmaceutically acceptable organic non-toxic bases from which salts canbe formed include ion exchange resins such as, for example, arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

As used herein, the term “pharmaceutically acceptable non-toxic acids”,includes inorganic acids, organic acids, and salts prepared therefrom,for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

In practice, the compounds of the invention, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier can take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, and/or pharmaceutically acceptable salt(s) thereof, can alsobe administered by controlled release means and/or delivery devices. Thecompositions can be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention can include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of the compounds of the invention. The compounds of theinvention, or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moreother therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

In the treatment conditions which require negative allosteric modulationof metabotropic glutamate receptor activity an appropriate dosage levelwill generally be about 0.01 to 500 mg per kg patient body weight perday and can be administered in single or multiple doses. Preferably, thedosage level will be about 0.1 to about 250 mg/kg per day; morepreferably 0.5 to 100 mg/kg per day. A suitable dosage level can beabout 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, orabout 0.1 to 50 mg/kg per day. Within this range the dosage can be 0.05to 0.5, 0.5 to 5.0 or 5.0 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the from of tabletscontaining 1.0 to 1000 miligrams of the active ingredient, particularly1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500,600, 750, 800, 900 and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage of the patient to be treated. Thecompound can be administered on a regimen of 1 to 4 times per day,preferably once or twice per day. This dosing regimen can be adjusted toprovide the optimal therapeutic response.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors. Such factorsinclude the age, body weight, general health, sex, and diet of thepatient. Other factors include the time and route of administration,rate of excretion, drug combination, and the type and severity of theparticular disease undergoing therapy.

The present invention is further directed to a method for themanufacture of a medicament for modulating glutamate receptor activity(e.g., treatment of one or more neurological and/or psychiatric disorderassociated with glutamate dysfunction) in mammals (e.g., humans)comprising combining one or more disclosed compounds, products, orcompositions with a pharmaceutically acceptable carrier or diluent.Thus, in one aspect, the invention relates to a method for manufacturinga medicament comprising combining at least one disclosed compound or atleast one disclosed product with a pharmaceutically acceptable carrieror diluent.

The disclosed pharmaceutical compositions can further comprise othertherapeutically active compounds, which are usually applied in thetreatment of the above mentioned pathological conditions.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

F. Methods of Using the Compounds and Compositions

The amino acid L-glutamate (referred to herein simply as glutamate) isthe principal excitatory neurotransmitter in the mammalian centralnervous system (CNS). Within the CNS, glutamate plays a key role insynaptic plasticity (e.g., long term potentiation (the basis of learningand memory)), motor control and sensory perception. It is now wellunderstood that a variety of neurological and psychiatric disorders areassociated with dysfunctions in the glutamatergic system. Thus,modulation of the glutamatergic system is an important therapeutic goal.Glutamate acts through two distinct receptors: ionotropic andmetabotropic glutamate receptors. The first class, the ionotropicglutamate receptors, is comprised of multi-subunit ligand-gated ionchannels that mediate excitatory post-synaptic currents. Three subtypesof ionotropic glutamate receptors have been identified, and despiteglutamate serving as agonist for all three receptor subtypes, selectiveligands have been discovered that activate each subtype. The ionotropicglutamate receptors are named after their respective selective ligands:kainite receptors, AMPA receptors and NMDA receptors.

The second class of glutamate receptor, termed metabotropic glutamatereceptors, (mGluRs), are G-protein coupled receptors (GPCRs) thatmodulate neurotransmitter release or the strength of synaptictransmission, based on their location (pre- or post-synaptic). ThemGluRs are family C GPCR, characterized by a large (˜560 amino acid)“venus fly trap” agonist binding domain in the amino-terminal domain ofthe receptor. This unique agonist binding domain distinguishes family CGPCRs from family A and B GPCRs wherein the agonist binding domains arelocated within the 7-strand transmembrane spanning (7™) region or withinthe extracellular loops that connect the strands to this region. Todate, eight distinct mGluRs have been identified, cloned and sequenced.Based on structural similarity, primary coupling to intracellularsignaling pathways and pharmacology, the mGluRs have been assigned tothree groups: Group I (mGluR1 and mGluR5), Group II (mGluR2 and mGluR3)and Group III (mGluR4, mGluR6, mGluR7 and mGluR8). Group I mGluRs arecoupled through Gαq/11 to increase inositol phosphate and metabolism andresultant increases in intracellular calcium. Group I mGluRs areprimarily located post-synaptically and have a modulatory effect on ionchannel activity and neuronal excitability. Group II (mGluR2 and mGluR3)and Group III (mGluR4, mGluR6, mGluR7 and mGluR8) mGluRs are primarilylocated pre-synaptically where they regulate the release ofneurotransmitters, such as glutamate. Group II and Group III mGluRs arecoupled to Gαi and its associated effectors such as adenylate cyclase.

Post-synaptic mGluRs are known to functionally interact withpost-synaptic ionotropic glutamate receptors, such as the NMDA receptor.For example, activation of mGluR5 by a selective agonist has been shownto increase post-synaptic NMDA currents (Mannaioni et al., J. Neurosci.21:5925-5934 (2001)). Therefore, modulation of mGluRs is an approach tomodulating glutamatergic transmission. Numerous reports indicate thatmGluR5 plays a role in a number of disease states including anxiety(Spooren et al., J. Pharmacol. Exp. Therapeut. 295:1267-1275 (2000),Tatarczynska et al., Br. J. Pharmaol. 132:1423-1430 (2001)), addictionto cocaine (Chiamulera et al., Nature Neurosci. 4:873-874 (2001),Parkinson's disease (Awad et al., J. Neurosci. 20:7871-7879 (2000),Ossowska et al., Neuropharmacol. 41: 413-420 (2001), pain (Salt andBinns, Neurosci. 100:375-380 (2001)), and Fragile X syndrome (FXS) (see,e.g., de Vrij F M S, Levenga J, van der Linde H C, Koekkoek S K, DeZeeuw C I, Nelson D L, Oostra B A, Willemsen R: Rescue of behavioralphenotype and neuronal protrusion morphology in Fmr1 KO mice. NeurobiolDisease (2008) 31(1):127-132; Yan Q J, Rammal M, Tranfaglia M, BauchwitzR P: Suppression of two major Fragile X Syndrome mouse model phenotypesby the mGluR5 antagonist MPEP. Neuropharmacol (2005) 49(7):1053-1066.).

The disclosed compounds can be used as single agents or in combinationwith one or more other drugs in the treatment, prevention, control,amelioration or reduction of risk of the aforementioned diseases,disorders and conditions for which compounds of formula I or the otherdrugs have utility, where the combination of drugs together are safer ormore effective than either drug alone. The other drug(s) can beadministered by a route and in an amount commonly used therefore,contemporaneously or sequentially with a disclosed compound. When adisclosed compound is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchdrugs and the disclosed compound is preferred. However, the combinationtherapy can also be administered on overlapping schedules. It is alsoenvisioned that the combination of one or more active ingredients and adisclosed compound will be more efficacious than either as a singleagent.

In one aspect, the subject compounds can be coadministered withant-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, muscarinic agonists, muscarinic potentiators HMG-CoAreductase inhibitors, NSAIDs and anti-amyloid antibodies.

In a further aspect, the subject compounds can be administered incombination with sedatives, hypnotics, anxiolytics, antipsychotics,anti-epileptics, selective serotonin reuptake inhibitors (“SSRI”) and/orselective serotonin and norepinephrine reuptake inhibitors (“SSNRI”),tricyclic antidepressant drugs, monoamine oxidase inhibitors (MAOIs),5-HT2 agonists or antagonists, GlyT1 inhibitors and the like such as,but not limited to: risperidone, clozapine, olanzapine, haloperidol,fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and saltsthereof and combinations thereof.

In a further aspect, the subject compound can be used in combinationwith levodopa (with or without a selective extracerebral decarboxylaseinhibitor), anti-cholinergics such as biperiden, COMT inhibitors such asentacapone, A2a adenosine antagonists, cholinergic agonists, NMDAreceptor agonists or antagonists and dopamine agonists.

In a further aspect, the subject compound can be administered incombination with opiate agonists or antagonists, calcium channelantagonists, sodium channel antagonists, COX-2 selective inhibitors, NK1antagonists, non-steroidal anti-inflammatory drugs (“NSAID”), GABA-Areceptor modulators, dopamine agonists or antagonists, norepinephrinemodulators, nicotinic agonists or antagonists including nicotine, andmuscarinic agonists or antagonists. In a yet further aspect, the subjectcompound can be administered in combination with heroin substitutingdrugs such as methadone, levo-alpha-acetylmethadol, buprenorphine andnaltrexone, and disulfiram and acamprosate. In a further aspect, thesubject compound can be administered in combination with L-DOPA,buspirone, valproate, and gabapentin.

The pharmaceutical compositions and methods of the present invention canfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

1. Treatment Methods

The compounds disclosed herein are useful for treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with glutamatedysfunction. Thus, provided is a method of treating or preventing adisorder in a subject comprising the step of administering to thesubject at least one disclosed compound; at least one disclosedpharmaceutical composition; and/or at least one disclosed product in adosage and amount effective to treat the disorder in the subject.

Also provided is a method for the treatment of one or more neurologicaland/or psychiatric disorders associated with glutamate dysfunction in asubject comprising the step of administering to the subject at least onedisclosed compound; at least one disclosed pharmaceutical composition;and/or at least one disclosed product in a dosage and amount effectiveto treat the disorder in the subject.

Examples of disorders associated with glutamate dysfunction include:acute and chronic neurological and psychiatric disorders such ascerebral deficits subsequent to cardiac bypass surgery and grafting,stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia(including AIDS-induced dementia), Alzheimer's disease, Huntington'sChorea, amyotrophic lateral sclerosis, ocular damage, retinopathy,cognitive disorders, idiopathic and drug-induced Parkinson's disease,muscular spasms and disorders associated with muscular spasticityincluding tremors, epilepsy, convulsions, migraine (including migraineheadache), urinary incontinence, substance tolerance, addictivebehavior, including addiction to substances (including opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.), withdrawal from such addictive substances(including substances such as opiates, nicotine, tobacco products,alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), obesity,psychosis, schizophrenia, anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder), mooddisorders (including depression, mania, bipolar disorders), trigeminalneuralgia, hearing loss, tinnitus, macular degeneration of the eye,emesis, brain edema, pain (including acute and chronic pain states,severe pain, intractable pain, neuropathic pain, and post-traumaticpain), tardive dyskinesia, sleep disorders (including narcolepsy),attention deficit/hyperactivity disorder, and conduct disorder.

Anxiety disorders that can be treated or prevented by the compositionsdisclosed herein include generalized anxiety disorder, panic disorder,and obsessive compulsive disorder. Addictive behaviors include addictionto substances (including opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), withdrawal fromsuch addictive substances (including substances such as opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.) and substance tolerance.

Also provided is a method for treating or prevention anxiety,comprising: administering to a subject at least one disclosed compound;at least one disclosed pharmaceutical composition; and/or at least onedisclosed product in a dosage and amount effective to treat the disorderin the subject. At present, the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV) (1994, AmericanPsychiatric Association, Washington, D.C.), provides a diagnostic toolincluding anxiety and related disorders. These include: panic disorderwith or without agoraphobia, agoraphobia without history of panicdisorder, specific phobia, social phobia, obsessive-compulsive disorder,post-traumatic stress disorder, acute stress disorder, generalizedanxiety disorder, anxiety disorder due to a general medical condition,substance-induced anxiety disorder, and anxiety disorder not otherwisespecified.

Further disorders that can be treated or prevented by the compositionsdisclosed herein include Autism spectrum disorders, which areneuropsychiatric conditions characterized by widespread abnormalities ofsocial interactions and communication, as well as severely restrictedinterests and highly repetitive behavior. Autism spectrum disordersinclude Autism, Asperger syndrome, Childhood Disintegrative Disorders,Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS),sometimes called atypical autism, and Rett Syndrome. Fragile X syndrome(FXS) is a single gene disorder almost universally associated withsymptoms of autism spectrum disorder, the most common form of inheritedmental retardation, and the most common known cause of autism, affecting1 in 6,000 births. Therapeutic agents for treatment of patients with FXSare among the most critical of unmet medical needs, and there are veryfew proven effective treatment strategies for this patient population.Again, without wishing to be bound by theory, increasing evidence hasidentified a connection between the fragile X phenotype and mGluRsignaling

Compounds of the invention can be used, for example, for the treatmentof fragile X syndrome and autism spectrum disorder in a manner that canimprove symptoms (e.g., reduce anxiety and irritability; increasecognitive function, communication and/or social interaction). Thus, themethods of the invention can provide an effective manner to treat asubject having fragile X syndrome or autism spectrum disorder.

a. Treating a Disorder

In one aspect, the invention relates to a method for the treatment of adisorder associated with mGluR5 activity in a mammal comprising the stepof administering to the mammal at least one disclosed compound or atleast one disclosed product in a dosage and amount effective to treatthe disorder in the mammal. In a further aspect, the mammal is a human.In a further aspect, the mammal has been diagnosed with a need fortreatment of the disorder prior to the administering step. In a furtheraspect, the method further comprises the step of identifying a mammal inneed of treatment of the disorder.

In one aspect, the invention relates to a method for the treatment of adisorder associated with mGluR5 activity in a mammal comprising the stepof administering to the mammal at least one compound having a structurerepresented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein Q is CR^(6c) or N;wherein V is CR^(6b) or N; wherein W is CR⁶ or N; wherein Z is CR^(6a)or N; provided that 1-2 of Q, V, W, and Z are simultaneously N; R¹ isaryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R¹ issubstituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁶, when present, is selected from hydrogen, halogen, CN, C3-C4cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl;wherein R^(6a), when present, is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; whereinR^(6b), when present, is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R^(6c) isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, and C1-C6 haloalkoxy; wherein R⁷ is hydrogen, C1-C6 alkyl, orC1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl, C1-C6 cycloalkyl, amino,alkylamino, or dialkylamino; and wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; or a pharmaceuticallyacceptable salt thereof, in an effective amount to treat the disorder inthe mammal.

In a further aspect, L is O. In a still further aspect, R¹ is selectedfrom aryl and heteroaryl, each independently substituted with 0-3 of R⁹.

In a further aspect, the method of treatment wherein the compound has astructure represented by a formula:

wherein only one of W and Z is N. In a further aspect, the compoundwherein R¹ is selected from aryl and heteroaryl, each independentlysubstituted with 0-3 of R⁹.

In a further aspect, the compound administered is any disclosed compoundor a product of a disclosed method.

In a further aspect, the mammal is human. In a yet further aspect, themammal has been diagnosed with a need for treatment of the disorderprior to the administering step. In a still further aspect, thetreatment of the disorder further comprises the step of identifying amammal in need of treatment of the disorder. In an even further aspect,the disorder is a neurological and/or psychiatric disorder associatedwith glutamate dysfunction. In a further aspect, the disorder isselected from autism, addiction, anxiety, fragile x syndrome,gastroesophageal reflux disease (GERD), Parkinson's disease, and pain.

In a further aspect, the disorder is a disease of uncontrolled cellularproliferation. In yet further aspect, the uncontrolled cellularproliferation is cancer. In a still further aspect, the cancer isselected from breast cancer, renal cancer, gastric cancer, andcolorectal cancer. In yet further aspect, the cancer is selected fromlymphoma, cancers of the brain, genitourinary tract cancer, lymphaticsystem cancer, stomach cancer, larynx cancer, lung, pancreatic cancer,breast cancer, and malignant melanoma.

In a further aspect, mGluR5 activity is partially inhibited. In a stillfurther aspect, mGluR5 activity is totally inhibited. In a yet furtheraspect, the compound or product exhibits negative allosteric modulationwith an IC₅₀ of less than about 30×10⁻⁶.

In one aspect, the disorder is a neurological and/or psychiatricdisorder associated with glutamate dysfunction. In a further aspect, thedisorder is selected from addiction, affective disorder, age-relatedcognitive decline, Alzheimer's disease, amnestic disorders, amyotrophiclateral sclerosis, anxiety disorders, Angelmans's syndrome, Asperger'ssyndrome, attention deficit hyperactivity disorder, autism spectrumdisorders, bipolar disorder, brain edema, chronic pain, delirium,dementia, depression, diabetes, Down Syndrome, dystonia, eatingdisorders, epilepsy, fibromyalgia, fragile-X syndrome,Huntington's-related chorea, levadopa-induced dyskinesia,manic-depressive illness, migraine, movement disorders, multiplesclerosis, narcolepsy, neurofibromatosis type 1, neuropathic pain,obesity, pain, paranoia, Parkinson's disease, post-herpatic neuropathicpain, psychotic disorders, PTEN harmartoma syndrome, Rett syndrome,senile dementia, sleep disorder, substance-related disorder, or unipolardepression.

In one aspect, the disorder is a disease of uncontrolled cellularproliferation. In a further aspect, the disorder is cancer. In a furtheraspect, the disorder is glioblastoma, other astrocytomas, or anotherother form of cancer. In a further aspect, the disorder is selected frombreast cancer, renal cancer, gastric cancer, and colorectal cancer. In afurther aspect, the disorder is selected from lymphoma, cancers of thebrain, genitourinary tract cancer, lymphatic system cancer, stomachcancer, larynx cancer, lung, pancreatic cancer, breast cancer, andmalignant melanoma.

In a further aspect, mGluR5 activity is partially inhibited. In afurther aspect, mGluR5 activity is totally inhibited. In a furtheraspect, the compound or product exhibits negative allosteric modulationwith an IC₅₀ of less than about 30×10⁻⁶.

b. Decreasing mGluR5 Activity

In one aspect, the invention relates to a method for decreasing mGluR5activity in a mammal comprising the step of administering to the mammalat least one disclosed compound or at least one disclosed product in adosage and amount effective to decrease mGluR5 activity in the mammal.In a further aspect, the mammal is a human. In a further aspect, themammal has been diagnosed with a need for decreasing mGluR5 activityprior to the administering step. In a further aspect, the mammal hasbeen diagnosed with a need for treatment of a disorder related to mGluR5activity prior to the administering step. In a further aspect, themethod further comprises the step of identifying a mammal in need ofdecreasing mGluR5 activity.

In one aspect, the invention relates to a method for decreasing mGluR5activity in a mammal comprising the step of administering to the mammalat least one compound having a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein Q is CR^(6c) or N;wherein V is CR^(6b) or N; wherein W is CR⁶ or N; wherein Z is CR^(6a)or N; provided that 1-2 of Q, V, W, and Z are simultaneously N; R¹ isaryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R¹ issubstituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁶, when present, is selected from hydrogen, halogen, CN, C3-C4cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl;wherein R^(ha), when present, is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; whereinR^(6b), when present, is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R^(6c) isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, and C1-C6 haloalkoxy; wherein R⁷ is hydrogen, C1-C6 alkyl, orC1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl, C1-C6 cycloalkyl, amino,alkylamino, or dialkylamino; and wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; or a pharmaceuticallyacceptable salt thereof, in an effective amount to decrease mGluR5activity in the mammal.

In a further aspect, L is O. In a yet further aspect, R¹ is selectedfrom aryl and heteroaryl, each independently substituted with 0-3 of R⁹.

In a further aspect, the compound has a structure represented by aformula:

wherein only one of W and Z is N. In a still further aspect, R¹ isselected from aryl and heteroaryl, each independently substituted with0-3 of R⁹.

In a further aspect, the compound administered is any disclosed compoundor a product of a disclosed method.

In a yet further aspect, the compound is administered to a mammal,wherein wherein the mammal is a human. In a still further aspect, themammal has been diagnosed with a need for decreasing mGluR5 activityprior to the administering step. In an even further aspect, the mammalhas been diagnosed with a need for treatment of a disorder related tomGluR5 activity prior to the administering step. In a further aspect,the treatment further comprises the step of identifying a mammal in needof decreasing mGluR5 activity. In a yet further aspect, the decrease inmGluR5 activity treats a disorder associated with mGluR5 activity in themammal. In a still further aspect, the mammal has been diagnosed with aneed for treatment of the disorder prior to the administering step. Inan even further aspect, treatment further comprises the step ofidentifying a mammal in need of treatment of the disorder.

In a further aspect, the disorder is a neurological and/or psychiatricdisorder associated with glutamate dysfunction. In a still furtheraspect, the disorder is selected from autism, addiction, anxiety,fragile x syndrome, gastroesophageal reflux disease (GERD), Parkinson'sdisease, and pain.

In a further aspect, the disorder is a disease of uncontrolled cellularproliferation. In a yet further aspect, the uncontrolled cellularproliferation is cancer. In a still further aspect, cancer is selectedfrom breast cancer, renal cancer, gastric cancer, and colorectal cancer.In an even further aspect, the cancer is selected from lymphoma, cancersof the brain, genitourinary tract cancer, lymphatic system cancer,stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer,and malignant melanoma.

In a further aspect, mGluR5 activity is partially inhibited. In a stillfurther aspect, mGluR5 activity is totally inhibited. In a yet furtheraspect, the compound or product exhibits negative allosteric modulationwith an IC₅₀ of less than about 30×10⁻⁶.

C. Inhibiting mGluR5 Activity in Cells

In one aspect, the invention relates to a method for inhibiting mGluR5activity in at least one cell, comprising the step of contacting the atleast one cell with at least one disclosed compound or at least onedisclosed product in an amount effective to inhibit mGluR5 activity inthe at least one cell.

In one aspect, the invention relates to a method for inhibiting mGluR5activity in at least one cell, comprising the step of contacting the atleast one cell with at least one compound having a structure representedby a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein Q is CR^(6c) or N;wherein V is CR^(6b) or N; wherein W is CR⁶ or N; wherein Z is CR^(6a)or N; provided that 1-2 of Q, V, W, and Z are simultaneously N; R¹ isaryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R¹ issubstituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁶, when present, is selected from hydrogen, halogen, CN, C3-C4cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl;wherein R^(6a), when present, is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; whereinR^(6b), when present, is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R^(6c) isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, and C1-C6 haloalkoxy; wherein R⁷ is hydrogen, C1-C6 alkyl, orC1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl, C1-C6 cycloalkyl, amino,alkylamino, or dialkylamino; and wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; or a pharmaceuticallyacceptable salt thereof, in an effective amount to inhibit mGluR5activity in the at least one cell.

In a further aspect, L is O. In a yet further aspect, R¹ is selectedfrom aryl and heteroaryl, each independently substituted with 0-3 of R⁹.

In a further aspect, the compound has a structure represented by aformula:

wherein only one of W and Z is N. In a yet further aspect, R¹ isselected from aryl and heteroaryl, each independently substituted with0-3 of R⁹.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In a further aspect, the cell is mammalian. In a yet further aspect, thecell is human. In a still further aspect, the cell has been isolatedfrom a mammal prior to the contacting step. In an even further aspect,contacting the cell is via administration to a mammal. In a furtheraspect, inhibiting mGluR5 activity in the at least one cell decreasesmGluR5 activity in the mammal. In a yet further aspect, the decrease inmGluR5 activity in the mammal treats a disorder associated with mGluR5activity in the mammal.

In a further aspect, the disorder is a neurological and/or psychiatricdisorder associated with glutamate dysfunction. In a still furtheraspect, the disorder is selected from autism, addiction, anxiety,fragile x syndrome, gastroesophageal reflux disease (GERD), Parkinson'sdisease, and pain.

In a further aspect, the disorder is a disease of uncontrolled cellularproliferation. In a still further aspect, the uncontrolled cellularproliferation is cancer. In a yet further aspect, the cancer is selectedfrom breast cancer, renal cancer, gastric cancer, and colorectal cancer.In an even further aspect, the cancer is selected from lymphoma, cancersof the brain, genitourinary tract cancer, lymphatic system cancer,stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer,and malignant melanoma.

In a further aspect, mGluR5 activity is partially inhibited. In afurther aspect, mGluR5 activity is totally inhibited. In a furtheraspect, the compound or product exhibits negative allosteric modulationwith an IC₅₀ of less than about 30×10⁻⁶.

In a further aspect, the cell is mammalian, for example, human. In afurther aspect, the cell has been isolated from a mammal prior to thecontacting step. In a further aspect, contacting is via administrationto a mammal.

2. Use of Compounds

Also provided are the uses of the disclosed compounds and products. Inone aspect, the use relates to a treatment of a disorder in a mammal. Inone aspect, the use is characterized in that the mammal is a human. Inone aspect, the use is characterized in that the disorder is aneurological and/or psychiatric disorder associated with glutamatedysfunction. In one aspect, the use relates to negative allostericmodulation of metabotropic glutamate receptor activity in a mammal.

In one aspect, the invention relates to use of a compound having astructure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein W is CR⁶ or N;wherein Z is CR^(6a) or N; provided that only one of W and Z is N; R¹ isaryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R¹ issubstituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,lkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ is selectedfrom hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN; wherein R⁴is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino,CN, SO₂R⁸, and COR⁸, with the proviso that when A is N, then R⁴ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN,SO₂R⁸, and COR⁸; wherein R⁵ is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁶, when present,is selected from hydrogen, halogen, CN, C3-C4 cycloalkyl, C3-C4halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl; wherein each of R^(6a)and R^(6b) is independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; whereinR^(6c) is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl,C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R⁷ is hydrogen, C1-C6 alkyl,or C1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl, C1-C6 cycloalkyl, amino,alkylamino, or dialkylamino; and wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for thetreatment of a disorder associated with glutamate dysfunction in amammal.

In a further aspect, L is O. In a yet further aspect, R¹ is selectedfrom aryl and heteroaryl, each independently substituted with 0-3 of R⁹.

In a further aspect, the compound has a structure represented by aformula:

wherein only one of W and Z is N. In a yet further aspect, the structurewherein R¹ is selected from aryl and heteroaryl, each independentlysubstituted with 0-3 of R⁹.

In a further aspect, the compound exhibits partial or total inhibitionof mGluR5 response to glutamate as a decrease in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith rat mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound. In yet furtheraspect, the compound is any disclosed compound or product of a disclosedmethod.

In a further aspect, the disorder is a neurological and/or psychiatricdisorder. In a still further aspect, the disorder is selected fromautism, addiction, anxiety, fragile x syndrome, gastroesophageal refluxdisease (GERD), Parkinson's disease, and pain.

In a further aspect, the disorder is a disease of uncontrolled cellularproliferation. In a still further aspect, the uncontrolled cellularproliferation is cancer. In a yet further aspect, the cancer is selectedfrom breast cancer, renal cancer, gastric cancer, and colorectal cancer.In an even further aspect, the cancer is selected from lymphoma, cancersof the brain, genitourinary tract cancer, lymphatic system cancer,stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer,and malignant melanoma.

In a further aspect, mGluR5 activity is partially inhibited. In a stillfurther aspect, mGluR5 activity is totally inhibited. In a yet furtheraspect, the compound or product exhibits negative allosteric modulationwith an IC₅₀ of less than about 30×10⁻⁶.

In one aspect, the invention relates to the use of a disclosed compoundor a disclosed product in the manufacture of a medicament for thetreatment of a disorder associated with glutamate dysfunction in amammal. In a further aspect, the disorder is a neurological and/orpsychiatric disorder. In a further aspect, the disorder is a disease ofuncontrolled cellular proliferation.

3. Kits

In one aspect, the invention relates to a kit comprising at least onedisclosed compound or at least one disclosed product and one or more ofat least one agent known to increase mGluR5 activity; at least one agentknown to decrease mGluR5 activity; at least one agent known to treat aneurological and/or psychiatric disorder; at least one agent known totreat a disease of uncontrolled cellular proliferation; or instructionsfor treating a disorder associated with glutamate dysfunction. In afurther aspect, the at least one compound or the at least one productand the at least one agent are co-formulated. In a further aspect, theat least one compound or the at least one product and the at least oneagent are co-packaged.

In one aspect, the invention relates to a kit comprising at least onecompound having a structure represented by a formula:

wherein A is CR² or N; wherein L is O or NR⁷, wherein W is CR⁶ or N;wherein Z is CR^(6a) or N; provided that only one of W and Z is N; R¹ isaryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R¹ issubstituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸, with the proviso thatwhen A is N, then R⁴ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, and COR⁸;wherein R⁶, when present, is selected from hydrogen, halogen, CN, C3-C4cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl;wherein each of R^(6a) and R^(6b) is independently selected fromhydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6haloalkoxy; wherein R^(6c) is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R⁷is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl,C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino; and wherein eachR⁹, when present, is independently halogen, C1-C6 alkyl, C1-C6haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, NO₂, CN, SO₂R⁸,or COR⁸; or a pharmaceutically acceptable salt thereof, and one or moreof: at least one agent known to increase mGluR5 activity; at least oneagent known to decrease mGluR5 activity; at least one agent known totreat a neurological and/or psychiatric disorder; at least one agentknown to treat a disease of uncontrolled cellular proliferation; orinstructions for treating a disorder associated with glutamatedysfunction.

In a further aspect, the kit, wherein L is O. In a still further aspect,the compound of the kit, wherein R¹ is selected from aryl andheteroaryl, each independently substituted with 0-3 of R⁹.

In a further aspect, the kit, wherein the compound present is anydisclosed compound or at least one product of a disclosed method ofmaking.

In a further aspect, the kit comprises a disclosed compound or a productof a disclosed method.

In a further aspect, the at least one compound and the at least oneagent are co-formulated. In a still further aspect, the at least onecompound and the at least one agent are co-packaged.

The kits can also comprise compounds and/or products co-packaged,co-formulated, and/or co-delivered with other components. For example, adrug manufacturer, a drug reseller, a physician, a compounding shop, ora pharmacist can provide a kit comprising a disclosed compound and/orproduct and another component for delivery to a patient.

It is contemplated that the disclosed kits can be used in connectionwith the disclosed methods of making, the disclosed methods of using,and/or the disclosed compositions.

4. Non-Medical Uses

Also provided are the uses of the disclosed compounds and products aspharmacological tools in the development and standardization of in vitroand in vivo test systems for the evaluation of the effects ofpotentiators of mGluR related activity in laboratory animals such ascats, dogs, rabbits, monkeys, rats and mice, as part of the search fornew therapeutic agents of mGluR. In a further aspect, the inventionrelates to the use of a disclosed compound or a disclosed product aspharmacological tools in the development and standardization of in vitroand in vivo test systems for the evaluation of the effects ofpotentiators of mGluR5 related activity in laboratory animals such ascats, dogs, rabbits, monkeys, rats and mice, as part of the search fornew therapeutic agents of mGluR5.

G. EXPERIMENTAL

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Starting materials and therequisite intermediates are in some cases commercially available, or canbe prepared according to literature procedures or as illustrated herein.All ¹H NMR spectra were obtained on instrumentation at a field strengthof 300 to 500 MHz.

1. Route I

a. 4-(pyridin-3-yloxy)picolinonitrile (1)

4-Chloro-2-pyridine carbonitrile (1.0 g, 7.2 mmol, 1.0 eq),3-hydroxypyridine (686 mg, 7.21 mmol, 1.00 eq) and K₂CO₃ (1.2 g, 8.7mmol, 1.2 eq) were dissolved in DMF (10 mL) and heated in a microwavefor 15 minutes at 150° C. The reaction was cooled, diluted with EtOAcand washed with H₂O (3×). The organic layer was dried (MgSO₄), filteredand concentrated in vacuo. Purification by flash chromatography onsilica gel afforded 1.32 g (93%) of the title compound as a white solid:¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (d, J=5.8 Hz, 1H), 8.56 (m, 2H), 7.79(d, J=2.4 Hz, 1H), 7.75 (dt, J=8.4, 1.4 Hz, 1H), 7.55 (dd, J=8.3, 4.7Hz, 1H), 7.27 (dd, J=5.7, 2.4 Hz, 1H); ES-MS [M+1]⁺: 198.0.

b. 4-(pyridin-3-yloxy)picolinic acid (2)

Compound 1 (1.5 g, 7.6 mmol, 1.0 eq) was dissolved in ethanol (30 mL)and 1N NaOH (15 mL) was added. The mixture was refluxed for 18 h andafter cooling the reaction was neutralized with 1N HCl (15 mL) and thereaction was concentrated in vacuo. The crude reaction was dissolved in10% MeOH/CH₂Cl₂ and the undissolved salt was filtered off and thesolvents were removed in vacuo to afford the title compound as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J=2.7 Hz, 1H), 8.39-8.36 (m,2H), 8.06 (ddd, J=8.7, 2.7, 1.1 Hz, 1H), 7.88 (dd, J=8.7, 5.4 Hz, 1H),7.40 (d, J=2.2 Hz, 1H), 7.12 (dd, J=5.7, 2.4 Hz, 1H); ES-MS [M+1]⁺:217.1.

C. N-(4-methylthiazol-2-yl)-4-(pyridin-3-yloxy)picolinamide (3)

Compound 2 (3.0 g, 14 mmol, 1.0 eq), 4-methylthiazol-2-amine (1.66 g,14.5 mmol, 1.05 eq),2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (5.54 g, 14.5 mmol, 1.05 eq), and DIEA (2.6 mL, 15mmol, 1.1 eq) were dissolved in DMF (69 mL) and stirred overnight at rt.The reaction was diluted with EtOAc and washed with H₂O (2×). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo.Purification by preparative HPLC afforded 1.5 g (35%) of the titlecompound as an off-white powder: ¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (d,J=5.5 Hz, 1H), 8.59-8.57 (m, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.60-7.56 (m,2H), 7.31 (dd, J=5.5, 2.4 Hz, 1H), 6.89 (s, 1H), 2.29 (s, 3H); ES-MS[M+1]⁺: 313.1.

2. Route II

a. 3-bromo-5-(pyridin-3-yloxy)pyridine (4)

A mixture of 3-bromo-5-fluoropyridine (1.5 g, 8.5 mmol, 1.0 eq),3-hydroxypyridine (970 mg, 10.2 mmol, 1.20 eq), and potassium carbonate(1.8 g, 13 mmol, 1.5 eq) in DMF (30 mL) was heated at 200° C. for 30minutes in the microwave. The reaction mixture was diluted with 3M LiCland extracted (3×) with CH₂Cl₂. The combined organics were dried(MgSO₄), filtered, and concentrated in vacuo to give 2.0 g (94%) of thetitle compound as a brown liquid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d,J=1.8 Hz, 1H), 8.49 (d, J=2.8 Hz, 1H), 8.46-8.44 (m, 2H), 7.85 (t, J=2.2Hz, 1H), 7.60 (ddd, J=8.4, 2.9, 1.2 Hz, 1H), 7.48 (dd, J=8.4, 4.6 Hz,1H); ES-MS [M+1]⁺:251.0.

b. 5-(pyridin-3-yloxy)nicotinonitrile (5)

A mixture of polymer-bound triphenylphosphine (230 mg, 0.597 mmol, 0.150eq) and palladium(II) acetate (63 mg, 0.28 mmol, 0.070 eq) in DMF (12mL) stirred under argon at rt for 2 h. The supernatant DMF was removed,and fresh DMF (12 mL) was added. Compound 4 (1.0 g, 3.9 mmol, 1.0 eq)and zinc cyanide (470 mg, 4.00 mmol, 1.00 eq) were added, and the vialwas subjected to microwave irradiation at 150° C. for 25 minutes. Theresin was washed with ether, and the collected filtrate was washed (3×)with water and (1×) with brine. The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo. Purification by flashchromatography on silica gel afforded 780 mg (100%) of the titlecompound as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (d, J=1.4Hz, 1H), 8.74 (d, J=2.8 Hz, 1H), 8.51 (d, J=2.8 Hz, 1H), 8.47 (d, J=4.6Hz, 1H), 8.13 (t, J=2.1 Hz, 1H), 7.63 (ddd, J=8.4, 2.7, 1.1 Hz, 1H),7.49 (dd, J=8.5, 4.6 Hz, 1H); ES-MS [M+1]⁺:198.1.

C. 5-(pyridin-3-yloxy)nicotinic acid (6)

Compound 5 (450 mg, 2.28 mmol, 1.00 eq) was dissolved in Dioxane (15mL), and 1N NaOH (7.5 mL) was added. The reaction was stirred at 100° C.overnight. The reaction cooled to rt and was neutralized with 1N HCl(7.5 mL) and concentrated in vacuo. The concentrate was dissolved in 10%MeOH in CH₂Cl₂ and filtered. The filtrate was collected and concentratedin vacuo to afford 470 mg (94%) of the title compound as a tan solid: ¹HNMR (400 MHz, DMSO-d₆) δ 8.84 (d, J=1.4 Hz, 1H), 8.59 (d, J=2.8 Hz, 1H),8.49 (d, J=2.8 Hz, 1H), 8.45 (dd, J=4.6, 0.9 Hz, 1H), 7.71 (dd, J=2.6,1.7 Hz, 1H), 7.59 (ddd, J=8.4, 2.7, 1.2 Hz, 1H), 7.48 (dd, J=8.4, 4.6Hz, 1H); ES-MS [M+1]⁺:217.1.

d. N-(4-methylthiazol-2-yl)-5-(pyridin-3-yloxy)nicotinamide (7)

Compound 6 (30 mg, 0.14 mmol, 1.0 eq), 4-methylthiazol-2-amine (19 mg,0.17 mmol, 1.2 eq),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (110 mg, 0.289 mmol, 2.10 eq), andN,N-Diisopropylethylamine (38 mg, 0.29 mmol, 2.1 eq) were dissolved inCH₂Cl₂ (1.5 mL) and DMF (0.30 mL) and stirred at rt for 72 h. Thereaction was quenched with water, and the layers were separated viaphase separation. The organic layer was dried on air concentrator andpurified by reverse-phase preparatory HPLC to afford 17 mg (38%) of thetitle compound as a mono-TFA salt: ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (d,J=1.7 Hz, 1H), 8.69 (d, J=2.8 Hz, 1H), 8.56 (d, J=2.8 Hz, 1H), 8.49 (dd,J=4.7, 1.2 Hz, 1H), 8.04 (t, J=2.2 Hz, 1H), 7.68 (ddd, J=8.4, 2.8, 1.2Hz, 1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 7.23 (d, J=1.2 Hz, 1H), 2.36 (d,J=1.0, 3H); ES-MS [M+1]⁺:313.1.

3. Route III

a. benzyl 4-(pyrimidin-5-yloxy)picolinate (8)

4-(Pyrimidin-5-yloxy)picolinic acid (1.43 g, 6.58 mmol, 1.00 eq), benzylalcohol (1.02 mL, 9.88 mmol, 1.50 eq), PS—PPh₃ (5.51 g, 14.5 mmol, 2.20eq) and THF (66 mL) were added to a flame-dried round-bottom flask. Themixture was cooled to 0° C. and diisopropyl azodicarboxylate (2.07 mL,10.5 mmol, 1.60 eq) was added dropwise. The reaction was allowed to warmto rt and stirred for 1 h. The reaction was filtered and washed withEtOAc. The combined organics were concentrated in vacuo and purified byflash chromatography on silica gel to afford 750 mg (37%) of the titlecompound as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 9.16 (s, 1H), 8.87(s, 2H), 8.64 (d, J=5.7 Hz, 1H), 7.66 (d, J=2.5 Hz, 1H), 7.47-7.40 (m,2H), 7.40-7.38 (m, 1H), 7.38-7.32 (m, 3H), 5.36 (s, 1H); [M+1]⁺: 308.1.

b. N-(6-methylpyridin-2-yl)-4-(pyrimidin-5-yloxy)picolinamide (9)

2-Amino-6-picoline (49 mg, 0.45 mmol, 2.0 eq) was dissolved in THF (0.55mL) in a flame-dried round bottom flask. A 0.5 M solution of potassiumbis(trimethylsilyl)amide in toluene (943 μL, 0.453 mmol, 2.00 eq) wasadded dropwise and the reaction was stirred for 5 min. Compound 8 (69mg, 0.22 mmol, 1.0 eq) was added as a solution in THF (0.55 mL) and thereaction was stirred for 30 min. The reaction was diluted with EtOAc,neutralized with 1N HCl and washed with water. The organic layer wasdried (MgSO₄), filtered and concentrated in vacuo. Purification by flashchromatography on silica gel afforded 45 mg (65%) of the title compoundas an off-white solid: ¹H NMR (400 MHz, CDCl₃) δ 10.32 (s, 1H), 9.19 (s,1H), 8.92 (s, 2H), 8.69 (d, J=5.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H),7.82-7.75 (m, 1H), 7.71 (d, J=2.5 Hz, 1H), 7.42 (dd, J=5.6, 2.6 Hz, 1H),7.07 (d, J=7.2 Hz, 1H), 2.43 (s, 3H); [M+1]⁺: 308.2.

4. Route IV

a. 4-(pyridin-3-ylamino)picolinonitrile (10)

4-Chloro-2-pyridinecarbonitrile (1 g, 7 mmol, 1 eq), 3-aminopyridine(0.815 mg, 8.66 mmol, 1.20 eq), Cs₂CO₃ (3.29 g, 10.1 mmol, 1.40 eq),Pd₂(dba)₃ (332 mg, 0.577 mmol, 0.0800 eq),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (501 mg, 0.866 mmol,0.120 eq) and dioxane (18 mL) were added to a microwave vial. The vialwas purged with argon, capped and heated at 100° C. for 18 h. Aftercooling the reaction was filtered over a plug of celite and the plug waswashed with 5% MeOH/CH₂Cl₂. The solvents were removed in vacuo and thecrude mixture was purified by flash chromatography on silica gelafforded 1.374 g (97%) of the title compound as an orange solid: ¹H NMR(400 MHz, CDCl₃) δ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H), 8.49 (d,J=2.6 Hz, 1H), 8.34-8.31 (m, 2H), 7.73 (dq, J=1.3, 8.2 Hz, 1H),7.43-7.40 (m, 1H), 7.39 (d, J=2.3 Hz, 1H), 7.13 (dd, J=2.4, 5.9 Hz, 1H);ES-MS [M+1]⁺:197.1.

b. 4-(methyl(pyridin-3-yl)amino)picolinonitrile (11)

NaH (185 mg, 7.71 mmol, 1.10 eq) was added to a flame-dried round-bottomflask and anhydrous THF (17.5 mL) was added. The slurry was cooled to 0°C. and compound 10 (1.374 g, 7.003 mmol, 1.000 eq) was added as asolution in THF (17.5 mL). After stirring at 0° C. for 30 minutes methyliodide (481 μL, 7.71 mmol, 1.10 eq) was added and the reaction wasallowed to warm to room temperature while stirring overnight. Thereaction was diluted with EtOAc and washed with water (1×). The aqueouslayer was back extracted (1×) with EtOAc and the combined organics werewashed with brine, dried (MgSO₄), filtered and concentrated in vacuo.Purification by flash chromatography on silica gel afforded 473 mg (32%)of the title compound as a white solid: ¹H NMR (400 MHz, CDCl₃) δ¹H NMR(400 MHz, DMSO-d₆) δ 8.58 (d, J=2.5 Hz, 1H), 8.56 (dd, J=1.2, 4.7 Hz,1H), 8.24 (d, J=6.0 Hz, 1H), 7.81 (dq, J=1.4, 8.2 Hz, 1H), 7.56-7.53 (m,1H), 7.25 (d, J=2.6 Hz, 1H), 6.80 (dd, J=2.7, 6.0 Hz, 1H), 3.36 (s, 3H);ES-MS [M+1]⁺:211.1.

C. 4-(methyl(pyridin-3-yl)amino)picolinic acid (12)

Compound 11 (0.473 g, 2.25 mmol, 1.00 eq) was dissolved in ethanol (10mL) and 1N NaOH (5 mL) was added. The mixture was refluxed for 18 h andafter cooling the reaction was neutralized with 1N HCl (5 mL) and thereaction was concentrated in vacuo. The crude reaction was dissolved in10% MeOH/CH₂Cl₂ and the undissolved salt was filtered off and thesolvents were removed in vacuo to afford 0.461 g (89%) of the titlecompound as a tan solid: ¹H NMR (400 MHz, CDCl₃) δ8.65-8.61 (m, 2H),8.12 (d, J=6.7 Hz, 1H), 7.88 (ddd, J=8.1, 2.5, 1.6 Hz, 1H), 7.60 (dd,J=8.2, 4.8 Hz 1H), 7.4 (d, J=2.9 Hz, 1H), 6.88 (dd, J=6.7, 2.9 Hz, 1H),3.46 (s, 3H); [M+1]⁺: 230.2.

d. 4-(methyl(pyridin-3-yl)amino)-N-(4-methylthiazol-2-yl)picolinamide(13)

Compound 12 (0.1 g, 0.4 mmol, 1 eq), 4-methylthiazol-2-amine (60 mg,0.53 mmol, 1.2 eq),2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (348 mg, 0.915 mmol, 2.10 eq), and DIEA (160 μL,0.915 mmol, 2.10 eq) were dissolved in CH₂Cl₂ (5 mL) and DMF (1 mL) andstirred rt for 48 h. The reaction was diluted with CH₂Cl₂ and washedwith water (1×). The organics were dried (MgSO₄), filtered andconcentrated in vacuo. Purification by flash chromatography on silicagel afforded 35 mg (25%) of the title compound as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 8.60 (d, J=2.3 Hz, 1H), 8.56 (dd, J=4.7, 1.1 Hz, 1H),8.33 (d, J=4.8 Hz, 1H), 7.83 (ddd, J=8.2, 2.4, 1.5 Hz, 1H), 7.55 (dd,J=8.1, 4.7 Hz, 1H), 7.31 (s, 1H), 6.94-6.89 (m, 1H), 8.86 (s, 1H), 3.40(s, 3H), 2.28 (s, 3H); [M+1]⁺: 326.2.

5. Metabotropic Glutamate Receptor Activity Assay

The utility of the compounds in accordance with the present invention asnegative allosteric modulators of metabotropic glutamate receptoractivity, in particular mGluR5 activity, can be demonstrated bymethodology known in the art. Human embryonic kidney (HEK) cellstransfected with rat or human mGluR5 were plated in clear bottom assayplates for assay in a Functional Drug Screening System (FDSS). The cellswere loaded with a Ca2+-sensitive fluorescent dye (e.g., Fluo-4), andthe plates were washed and placed in the FDSS instrument. Test compoundwas applied to cells 3 seconds after baseline readings were taken. Cellswere incubated with the test compounds for 140 seconds and thenstimulated with an EC₂₀ concentration of an mGluR5 agonist (e.g.,glutamate, 3,5-dihydroxyphenylglycine, or quisqualate); 60-80 secondslater an EC₈₀ concentration of agonist was added and readings taken foran additional 40 seconds. Data were collected at 1 Hz. Negativeallosteric modulation of the agonist response of mGluR5 by the compoundsin the present invention was observed as a decrease in response tonon-maximal concentrations of agonist (here, glutamate) in the presenceof compound compared to the response to agonist in the absence ofcompound. Concentration response curves were generated using a fourparameter logistical equation.

The above described assay was operated in two modes. In the first mode(utilizing a triple add protocol), a range of concentrations of thepresent compounds were added to cells, followed by two single fixedconcentrations of agonist (EC₂₀ followed by EC₈₀). If a compound actedas a potentiator, an EC₅₀ value for potentiation of the EC₂₀ responseand a maximum extent of potentiation by the compound at thisconcentration of agonist was determined by non-linear curve fitting. Ifa compound acted as an antagonist, an IC₅₀ value for antagonism of theEC₈₀ response and a maximum extent of antagonism by the compound at thisconcentration of agonist was determined by non-linear curve fitting. Inthe second mode (utilizing a double add protocol), several fixedconcentrations of the present compounds were added to various wells on aplate, followed by a range of concentrations of agonist for eachconcentration of present compound; the EC₅₀ values for the agonist ateach concentration of compound were determined by nonlinear curvefitting. A decrease in the EC₅₀ value of the agonist with increasingconcentrations of the present compounds (a leftward shift of the agonistconcentration-response curve) is an indication of the degree of mGluR5positive allosteric modulation at a given concentration of the presentcompound. An increase in the EC₅₀ value of the agonist with increasingconcentrations of the present compounds (a rightward shift of theagonist concentration response curve) is an indication of the degree ofmGluR5 antagonism at a given concentration of the present compound. Thesecond mode also indicates whether the present compounds also affect themaximum response to mGluR5 to agonists. Exemplary data are provided inTables 1 and 2 above.

6. Inhibition of Marble Burying in Mice Assay

It is well known that mice will bury foreign objects such as glassmarbles in deep bedding (Deacon, R. M. J. Nature Protocols 2006, 1,122-124). Low doses of anxiolytic benzodiazepines have been demonstratedto inhibit this behavior (Njung'e, K.; Handley, S. L. Brit. J.Pharmacol. 1991, 104, 105-112; Broekkamp, C. L.; Rijk, H. W.;Joly-Gelouin, D.; Lloyd, K. L. Eur. J. Pharmacol. 1986, 126, 223-229).Moreover, the known mGlu₅ NAMs MPEP(3-((2-Methyl-4-thiazolyl)ethynyl)-pyridine) and fenobam(1-(3-chlorophenyl)-3-(1-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)urea)are effective in this model (Spooren W. P. J. M.; Vassout A.; Neijt H.C.; Kuhn R.; Gasparini F.; Roux S.; Porsolt R. D.; Gentsch C. J.Pharmacol. Exp. Ther. 2000, 295, 1267-1275; Nicolas, L. B.; Kolb, Y.;Prinssen, E. P. M. Eur. J. Pharmacol. 2006, 547, 106-115). These factsalong with the relative convenience of this assay make it a useful invivo screening tool.

Doses of compound were suspended in vehicle (10% Tween 80 forintraperitoneal dosing and 0.5% methylcellulose for oral dosing),vortexed vigorously, heated gently with a Master Heat Gun (MasterAppliance Corp., Racine, Wis.), and sonicated at 37° C. for 30 minutes.The pH was checked using 0-14 EMD strips and adjusted to approximately7. All doses were administered at approximately 10 mL/kg.

Studies were conducted using male Harlan CD-1 mice (Harlan SpragueDawley, Indianapolis, Ind.), weighing 30 to 35 grams. Subjects werehoused in a large colony room under a 12 hour light/dark cycle (lightson at 6:00 a.m.) with food and water provided ad libitum. Test sessionswere performed between 10:00 a.m. and 4:00 p.m. All dose groupsconsisted of ≧7 mice. All experiments were conducted in accordance withthe National Institute of Health regulations of animal care covered inPrinciples of Laboratory Animal Care (National Institutes of Healthpublication 85-23, revised 1985) and were approved by the InstitutionalAnimal Care and Use Committee.

Plexiglass cages (32×17×14 cm) were arranged on top of a large, roundtable. Mice were transported from the colony room to the testing roomand allowed to habituate for 30 minutes. Mice were pretreated with adose of a standard compound (either MTEP or fenobam) or novel compoundfor 15 or 30 minutes and individually placed in the cages in which 12black glass marbles (14 mm diameter) had been evenly distributed (spaced6.4 cm vertically and 4.25 cm horizontally from each other and the wallsof the cage) on top of 2.5 cm Diamond Soft Bedding (Harlan Teklad,Madison, Wis.). The novel compound and comparator were evaluated in acounterbalanced design, in which all doses of compounds were tested ineach session. Mice receiving the same dose were placed in cages onopposite sides of the table to control for effects of lighting andcontext. Clear, perforated plastic lids were set on top of each cage andthe amount of marble burying was recorded over a 30 minute interval. Themice were then removed from the cages and the number of buried marbleswas counted using the criteria of greater than ⅔ covered by bedding.Each session was videotaped with a Sony MiniDV camcorder equipped with aSony wide-angle lens mounted on a 1.5 m tripod.

The data for the dose-response studies were analyzed by a between-groupanalysis of variance. If there was a main effect of dose, then each dosegroup was compared with the vehicle control group using a Dunnett'scomparison. The calculations were performed using JMP IN 8 (SASInstitute, Cary, N.C.) statistical software and graphed using SigmaPlot9(Sasgua, Ma.).

7. Inhibition of marble burying in mice byn-(4-methylthiazol-2-yl)-4-(Pyridin-3-yloxy)Picolinamide

Dose response activity ofN-(4-methylthiazol-2-yl)-4-(pyridin-3-yloxy)picolinamide in the marbleburying assay (mouse model of anxiolytic behavior) is shown in FIGS. 3and 4, and was carried out as described above. In FIG. 3, the assay wascarried out by dosing animals via intraperitoneal (“IP”) injection atthe doses indicated (mg/kg). Activity of the compound is compared to apositive control compound, MTEP, at the dose indicated. In FIG. 4, theassay was carried out by oral (“PO”) dosing of animals at the dosesindicated (mg/kg). Activity of the compound is compared to a positivecontrol compound, fenobam, at the dose indicated. Statisticallysignificant results (p<0.05) are indicated by an asterick above the bar.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A compound, or a pharmaceutically acceptable saltthereof, having a structure represented by a formula:

wherein A is CR² or N; wherein L is O, wherein W is CR⁶ or N; wherein Zis CR^(6a) or N; provided that only one of W and Z is N; wherein R¹ isaryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R¹ issubstituted with 0-3 of R⁹; wherein R² is hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸; wherein R³ isselected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;wherein R⁴ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, CN, SO₂R⁸, and COR⁸; wherein R⁵ is selectedfrom hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO₂R⁸, andCOR⁸; wherein R⁶, when present, is selected from hydrogen, halogen, CN,C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6haloalkyl; wherein R^(6a), when present, is selected from hydrogen,halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6haloalkoxy; wherein R^(6b) is selected from hydrogen, halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; whereinR^(6c) is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl,C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R⁷ is hydrogen, C1-C6 alkyl,or C1-C6 haloalkyl; wherein R⁸ is C1-C6 alkyl, C1-C6 cycloalkyl, amino,alkylamino, or dialkylamino; and wherein each R⁹, when present, isindependently halogen, C1-C6 alkyl, C1-C6 haloalkyl,C3-C4 cycloalkyl,C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino,alkylamino, dialkylamino, NO₂, CN, SO₂R⁸, or COR⁸.
 2. The compound ofclaim 1, wherein R¹ is selected from aryl and heteroaryl, eachindependently substituted with 0-3 of R⁹.
 3. The compound of claim 1,wherein R² is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.
 4. The compound of claim1, wherein R³ is halogen, C1-C6 alkyl, C1-C6 haloalkyl, or CN.
 5. Thecompound of claim 1, wherein R⁴ is hydrogen, halogen, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
 6. The compound of claim1, wherein R⁵ is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or CN.7. The compound of claim 1, wherein R⁶ is selected from hydrogen,halogen, and CN.
 8. The compound of claim 1, wherein R⁷ is hydrogen. 9.The compound of claim 1, wherein R⁸ is selected from amino, alkylamino,and dialkylamino.
 10. The compound of claim 1, wherein at least one R⁹is present and each R⁹ is independently selected from halogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and CN.